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Kelsey Moody on Antoxerene and the Near Future of Applied Aging Research

Antoxerene formally launched today, concurrently with a $1.5 million funding round, a spin-off venture of Ichor Therapeutics. I recently had the chance to ask Kelsey Moody at Ichor Therapeutics a few questions on the new lines of work that will proceed under the Antoxerene umbrella, as well as his thoughts on the current state of the industry; I think you'll find those interesting. It looks like involvement in the growing senolytics industry is on the cards, and why not? That market will be enormous, with room for many companies and classes of therapy.

As you'll no doubt recall, the staff at Ichor Therapeutics are working on an implementation of technology developed at the SENS Research Foundation with the intent of removing age-related metabolic waste that contributes to macular degeneration. They have a broad range of aspirations beyond this goal, however. When the technology at the heart of Antoxerene was first pointed out to me, a while back, the core of the thing was a novel approach to protein manufacture, just getting started on the long road of commercial development. Infrastructural improvements of this nature are what drive progress in the long term: they are essential to the process of making the various potential applications of scientific progress cheap enough and reliable enough to be practical. This new technology has since been brought into the fold for uses relevant to the development of therapeutics to treat the causes of aging, and that initiative wrapped into the company now called Antoxerene.

Antoxerene has the look of a sizable expansion of the work at Ichor Therapeutics. Could you give an overview of the initiative?

Antoxerene is a pharmaceutical company that develops small molecule drugs for pathways of aging. Many protein-protein interactions are known to contribute to the onset and progression of age-associated disease. One such example is p53. p53 is a master cell regulator that should force apoptosis in cells that become cancerous or senescent. Cancer is obviously a major disease of aging. Senescent cells are non-dividing pro-inflammatory cells that exacerbate or may even cause many diseases of aging. A common feature of both cancerous cells and senescent cells is the ability to inhibit p53. Many cancers achieve this by overexpressing a protein called MDM2, which binds p53. Similarly in senescent cells, a protein called FOXO4 is overexpressed which binds p53. In both cases, p53 is prevented from performing its function and cells that should be eliminated from the body are allowed to persist. One of our goals is to identify small molecules that can disrupt these interactions and reactivate p53. These leads can then be developed as highly targeted drugs to treat cancers and diseases of cellular senescence.

What is it about the underlying protein production technology that makes now a great time to be undertaking this drug discovery work?

Antoxerene is following a traditional small molecule drug discovery path, but we have advanced the state of the art. The typical workflow for drugging a pathway is to manufacture large quantities of the proteins of interest (for example, p53 and FOXO4), then test a library of compounds to identify "hits" that stop the proteins from binding. However, protein manufacturing is often non-trivial, and large quantities of protein are required for a high throughput screen. Complicated proteins like p53 cannot be made using inexpensive microbial systems like E. coli because these bugs lack essential machinery found in mammalian cells. Expression within mammalian systems is possible, but cannot be scaled cost effectively. Because of this, the state of the art for drug discovery is to use small fragments of the proteins of interest, rather than full-length protein. Of course, this is analogous to evaluating a used car by looking at a hubcap. It may or may not accurately depict the state of the entire car.

Under a co-development deal with Finger Lakes Bio, Antoxerene has used proprietary RecombiPure expression technology to manufacture full-length, properly folded, bioactive proteins at scale in E. coli. While everyone else is looking at hubcaps, we see the entire car.

One of your Antoxerene development projects, BuckyProtector, is an antioxidant. Antioxidants have a decidedly mixed history when it comes to therapeutic application and aging. What is new and different here?

BuckyProtector is a combination moon-shot / community service project. Back in 2012, Baati et al described a profound decrease in all-cause mortality in rats that were fed a fullerene formulation. No group has replicated those findings, but a number of people have begun consuming this product from various online vendors. In our hands, we find tremendous variance in the formulation from vendor to vendor, and none of the vendors we contacted were able to provide quality assurance data that support label claims of contents and purity. Preliminary studies suggest that some of these formulations may be highly toxic. We have brought proper manufacturing and quality control in house and are working to definitively answer whether development of a fullerene therapeutic is worthy of a serious translational effort. We hope to have more to report on this front in the coming months.

I see that FOXO4-p53 is on the list of targeted mechanisms. Is Ichor getting into the senescent cell clearance field in a significant way? What do you think of the prospects for this area of development?

Our interest in the senescent cell clearance field will largely depend on what we find during our initial screens. However, we are open to the idea of having a significant focus in the space. The field is heating up, and we have specific expertise in drugging p53 pathway interactions that make us uniquely suited to take on a discovery initiative around FOXO4-p53. This seems like an area where we can make a large impact in a cost effective and timely manner.

The last few years have seemed very positive from the point of view of progress towards the treatment of aging, in terms of gaining support and building working technology. What are your predictions for the next five to ten years?

This is difficult to predict because it is unclear to me what impact the tech sector will have on the life sciences, and drug development in general. What I have observed over the past 3-5 years is a growing interest among software and tech entrepreneurs and investors in the life sciences, and the aging space in general. Some companies, such as BioAge Labs and Insilico Medicine, are looking to apply modern computational approaches to drug discovery, with a focus on aging. Others, such as Unity Biotechnology or Oisin Biotechnologies, are pursuing more traditional translational research initiatives, but with substantial financial support from tech investors. We even see a number of software and tech entrepreneurs entering the life sciences, such as with Immusoft.

It is uncertain what levels of success these companies will achieve, but I am optimistic. To the best of my understanding these are well thought out initiatives being led by strong teams. However, there is a tendency for some people from the software and tech sectors to think biology is a coding problem that can be solved by throwing money at it, and seem to gravitate towards personalized health, synthetic biology, biohacking, and similar initiatives. This is great for driving interest in aging research or developing a profitable consumer product, but when lofty expectations are met with the harsh reality of bench science, particularly in drug development, there is a high risk that ambitions will be stifled.

The Ellison Medical Foundation was an early example of this. Up to $40 million per year was spent on aging research starting in 1998. With relatively little to show for it, the program was concluded in 2013. It is not sufficient to throw money at research problems, particularly when drug discovery is the goal. And this is a trap high net worth individuals seem to repeatedly fall into. The basic science, medicinal chemistry, toxicology, formulation work, regulatory pathway, clinical trials, IP strategy, and business strategy all rely upon incredibly divergent skill sets. It is rare to find a team that possesses all of them. New investors in particular should be grilling entrepreneurs on the details of these points, not getting caught up in the hype of cool technology (though the latter is certainly the more fun part).

All that said, collectively I believe the future for the treatment of aging is bright. Aging research is becoming a mainstream discipline as the research questions are becoming clearer. "How do we cure aging?" doesn't fly. Better questions lead to better answers. "What level of therapeutic efficacy will be achieved for disease X with a targeted FOXO4-p53 drug that selectively eliminates senescent cells?" We hope to find out.

How can our community help Ichor to succeed in this latest venture?

By writing. Ichor has a great opportunity to begin leveraging NY government programs for funding, tax incentives, and exposure. If pursued properly, these can do an enormous amount to leverage investor funding and promote public interest in aging research. There are not a lot of players in the Syracuse area where we operate, and we are getting noticed. Letters from the community will help. It does not matter where you live. Type or write two copies of a letter made out to Senator John DeFrancisco and Rob Simpson and physically mail it to Senator John DeFrancisco's Syracuse office or Rob Simpson's Syracuse office respectively.

Tell them that you read about the exciting new research Ichor Therapeutics is doing in Syracuse. Tell them that their Grants for Growth program provided essential seed funding for getting both of Ichor's initiatives (Lysoclear and Antoxerene) off the ground, and raise millions of dollars in follow-on funding. Tell them that you are excited to see people in government taking an active role in promoting medical research on age-related disease, particularly start-ups. Tell them that you wish your government would do the same. Tell them that you hope they continue to support companies like Ichor in the Syracuse region. It is important that these letters be "mainstream" friendly. Ichor is not curing aging. We are developing first in class drugs for age-associated disease. It doesn't have to be long or fancy, but in a small city like Syracuse, your letters will be noticed. They will matter. They will drive decisions.

Comments

Small molecule drugs against Alzheimers? Well, they are certainly fearless then, as that dragon has eaten a lot of brave companies!

Are there any further reading materials/papers on the RecombiPure tech other than the blurb on the website?

"Using proprietary RecombiPure (RP) protein expression technology, Antoxerene is able to recombinantly express hard or impossible to manufacture protein targets in a full-length, biologically active form. The basis of this technology is a combination solubility/affinity tag derived from a thermophile. Due to its thermophilic origin, the tag is stable, inexpensive, small, and possesses antibody level binding affinities."

Also, I like Kelsey Moody's flinty, no nonsense, utterly unsentimental attitude. It is a nice contrast to some of the woo-woo wooliness and lack of an actual credible chain of reasoning seen at events such as Raadfest, or even things like Liz Parish and Bioviva which have an air of quackery about them.

Posted by: Jim at August 23rd, 2017 8:56 PM

Kelsey, would you mind detailing your Fullerene production or will it be kept secret now that you are "in the business"?

Posted by: arren brandt at August 24th, 2017 7:46 AM

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