An Interview with Matthew O'Connor, as Underdog Pharmaceuticals Secures Seed Funding

Matthew O'Conner presented at Undoing Aging earlier this year on the startup biotech company Underdog Pharmaceuticals. The company is spinning out of the SENS Research Foundation (SRF), based on research conducted by the scientific team there in recent years. The company is focused on a class of molecule known cyclodextrins, and have candidates capable of efficiently binding and sequestering 7-ketocholesterol. This form of oxidized cholesterol is of great importance to the progression of atherosclerosis, and possibly other age-related conditions as well. In the case of atherosclerosis, the presence of oxidized cholesterols, and particularly 7-ketocholesterol, causes the macrophage cells, which are responsible for clearing out cholesterol from blood vessel walls, to become dysfunctional and inflammatory. Remove the 7-ketocholestrol, and the problem should largely go away.

I'm pleased to note that Underdog Pharmaceuticals has secured nearly $4 million in seed funding, and is thus well set to move ahead with the clinical development of this approach over the next few years. I would hope that this will be one of numerous biotech companies focused on rejuvenation research to emerge directly from the SENS Research Foundation in-house programs, joining the many others that have emerged within the broader network of researchers and entrepreneurs interested in tackling causes of aging. To mark the occasion, I recently had the chance to chat with Matthew O'Conner about Underdog Pharmaceuticals; as you can see, the company is a demonstration in and of itself of how the networks built by the foundation over the past decade have matured.

Underdog Pharmaceuticals, Inc. (Underdog), and SENS Research Foundation (SRF) today announced the launch of Underdog and the completion of its seed round, providing $3.95 million to promote Underdog's development of disease-modifying treatments for atherosclerosis and other age-related diseases. SRF also announced two senior appointments. The Underdog round is led by Michael Greve's Kizoo Technology Capital, part of the Forever Healthy Group and one of the premier organizations focusing on accelerating rejuvenation biotechnologies.

Underdog was built from an SRF flagship program that has driven two years of applied development designed to explore and repair the underlying causes of cardiovascular disease. Its co-founders are Matthew O'Connor, Ph.D. and Michael Kope, formerly the V.P. of Research and the founding CEO, respectively, of SRF. "We've taken a well-known and extremely safe compound, and have created novel derivatives that can specifically target the toxic biomolecule that drives the development of atherosclerosis, the cause of most heart attacks and strokes." Underdog's research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function.

Who are the Underdog Pharmaceuticals team, and how did you all become involved in this business of defeating atherosclerosis?

Underdog is being co-founded by Michael Kope and myself, formerly the founding CEO and VP of Research, respectively, of SRF. We are exiting our decade-long service at SRF to do this. We are building a great team of researchers and partners including our home-grown computational chemist Amelia Anderson and veteran bench industry biologists Daniel Clemens and Tamari Kirtadze. We are partnering with Cyclolab LTD for cyclodextrin chemistry expertise, MD.USE for cyclodextrin computational chemistry, and Biolacuna for regulatory affairs.

Amelia Anderson was one of our elite SRF Summer Scholars two years ago. It was that summer that she conceived of our computational chemistry program and started to build it. Dave Brindley, founder of Biolacuna, was the first SRF-sponsored PhD student and has since become a world-renowned biomedical regulatory expert specializing in developing methods for gaining approval of the new classes of rejuvenation biotechnologies that are going to be needed to revolutionize medicine. SRF's investment in education is really coming home to help us.

Every name has a story, why Underdog Pharmaceuticals?

We chose the name Underdog to connote our core mission - to attack the underlying causes of age-related disease; and also to represent the broader fight as the underdog seeking to overturn the current costly and inefficient paradigm for the treatment of such diseases ... and because Mike and I couldn't otherwise agree on whose dog to name the company after.

You outlined the science behind Underdog at Undoing Aging earlier this year, but if you could give a summary for the audience here?

We are targeting 7-ketocholesterol (7KC) in aging and disease. 7KC is a toxic oxysterol formed by the reaction of a cholesterol molecule with an oxygen free radical. 7KC has no redeeming qualities and is difficult to clear once it has become lodged in a cell. It is highly toxic to cells and as a fundamental damage molecule implicated many diseases of aging including atherosclerosis (and therefor heart attacks and strokes), Alzheimer's disease, and macular degeneration. We are engineering cyclodextrins to bind 7KC with high affinity and specificity. Cyclodextrins are cyclic sugar molecules that are very safe and amenable to engineering. We have created a new class of cyclodextrins that can bind 7KC more than ten times better than any other cyclodextrin currently available. The goal is to remove 7KC from cells and tissues and have it be excreted from the body.

Do you plan to work towards sequestration of other molecular targets via cyclodextrins, now that you've demonstrated success with one?

Yes! The tools that we are developing are quite amenable to targeting other damage molecules with cyclodextrins. Particularly the cyclodextrin computational platform that we are developing can easily be adapted for other targets; as well as our automated cyclodextrin screening tool and safety testing assays. For at least the next few years, however, we'll be spending 99% of our time and energy on getting our first drug to the clinic.

SENS Research Foundation is a non-profit, Underdog Pharmaceuticals is a startup; has it been challenging to make the shift to the for-profit world?

It has not. SRF's mission has always been to bring the promise of rejuvenation biotechnologies to real-life people. The organization has always known that successful technology transfer is inherent and intimate to that mission. SRF has always been looking for opportunities for translation with all of our projects. With respect to Underdog this transition for us has been been super fun. We've been delighted with the response to our research from the scientific community, discussions with financial agents, and with our development collaborators all around the world. We have an exciting message and it's been gratifying to see how enthusiastically it's been received. Our investors are all enthusiastic about our mission which is why we've been able to raise the funds that we need and transition so quickly into this new company.

Is this the starting point for SENS Research Foundation to become an incubator of a series of biotech startups?

SRF won't be developing wholly owned subsidiaries; it will be creating companies using the same rubric as university tech transfer programs. As with Underdog, SRF would have both royalty and equity interests in such companies. It is inherent to the mission that SRF tries to do this to make these technologies publicly available, and indeed we think one sees evidence of that both in the success of this spinout and in the new leadership that's been chosen for SRF. Jim O'Neill is the new interim CEO at SRF. He has an extensive background in both government research funding and private investment and is committed to driving this push towards translating SRF technologies into therapies. Professor Alexandra Stolzing is coming on board to replace me as VP of Research. Her reputation in rejuvenation / regenerative medicine should need no introduction, but she has played both faculty and private industry leadership roles focused on translational medicine in aging. SRF is in the process of reviewing incubator and accelerator programs focused on translating SENS-style damage repair technologies. We'd love to see them do more of that!

Will we see the allotopic expression project spun out in the same way?

The MitoSENS allotopic expression project is plowing ahead. It started as a basic research program but has made great strides and could be ready to make a transition to the treatment of mitochondrial genetic disease quite soon.

If this all works out amazingly well, atherosclerosis is much reduced, and Underdog Pharmaceuticals becomes a billion dollar company, what next?

Well we want to not only reduce atherosclerosis, but eliminate it entirely! But on a broader scale our team genuinely hopes to be able to contribute to a change in paradigm, from both a regulatory perspective and a clinical perspective, on how we treat diseases of aging. This could be a long-term challenge, and if done appropriately, we, together with other companies with similar missions, can work with regulatory agencies to look at age-related disease in a new way. This is a big part of the reason that we want to do this company now.


Very interesting interview! Thanks!

Posted by: Antonio at November 15th, 2019 2:57 AM

Underdog's PR Blob: '...7-ketocholesterol, which are broadly toxic molecules with no known biological function.'

The linked PubChem entry for 7-ketocholesterol in Reason's comment says:

'7-ketocholesterol ... It has a role as a neuroprotective agent.'

Neuroprotective is no biological function? Interesting.

Posted by: Jones at November 15th, 2019 5:15 AM

This will likely be more effective than statins. Is AtheroSENS a new arm of the SENS platform?

Posted by: thomas.a at November 15th, 2019 6:07 AM

@thomas.a: SENS is divided by treatment type, not disease name. Thus, all aggregates inside cells that can be eliminated in principle by binding its components to enzymes or other molecules the body doesn't naturally produce, belong to LysoSENS.

Posted by: Antonio at November 15th, 2019 6:56 AM

This is fantastic. I hope they make great progress; I'd sure like to say "Goodbye" to statins and all their quality of life reducing side effects.

Posted by: bmack500 at November 15th, 2019 12:10 PM

Very encouraging, thanks!

Posted by: Nicolai at November 15th, 2019 4:29 PM

Sounds great. What is an approximate timeframe to get a first agent out?

Posted by: Chris at November 15th, 2019 5:01 PM

The main thing is that this drug does not have side effects. It is known that although cyclodextrin reduces the accumulation of cholesterol and lipids, which makes it possible to treat Nyman-Peak type C disease, Alzheimer's disease and atherosclerosis, this treatment is accompanied by a negative side effect in the form of hearing loss.
Crumling MA, Liu L, Thomas PV, Benson J, Kanicki A, Kabara L, et al. (2012). Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin. PLoS ONE 7(12): e53280. DOI:10.1371/journal.pone.0053280

Pilely, K., Bakke, S. S., Palarasah, Y., Skjoedt, M. O., Bartels, E. D., Espevik, T., & Garred, P. (2019). Alpha-cyclodextrin inhibits cholesterol crystal-induced complement-mediated inflammation: A potential new compound for treatment of atherosclerosis. Atherosclerosis, 283, 35-42. PMID 30772772

Posted by: Dmitry Dzhagarov at November 17th, 2019 5:22 AM


Perhaps it doesn't permeate the blood-brain barrier? Just speculating.

Posted by: bmack500 at November 18th, 2019 7:50 AM

@Dmitry Dzhagarov - cyclodextrans have already been approve for human consumption:

"The oral administration of HP-β-CD at daily doses of 16-24 g for 14 days to human volunteers, however, resulted in an increased incidence of soft stools and diarrhea. Based on these clinical studies, HP-β-CD is considered to be nontoxic if the daily dose is < 16 g (270 mg/kg) [22]."

Posted by: jimofoz at November 18th, 2019 10:32 AM


And since they induce diarrhea in large doses they can lead to forced calorie restriction...

Posted by: Cuberat at November 18th, 2019 11:08 AM

I wonder if cyclodextrans could be made to target specificially created tattoo inks, enabling "permanent" tattoos to be later removed by a local injection of these cyclodextrans when no longer wanted?

Underdog probably don't have the resources to investigate this, but maybe someone there could pursue it as a side project, as anything to do with cosmetic medicine and the skin tends to get a lot of media attention (look at the popular coverage of when it is reported that a treatment could also turn grey hair coloured again).

Spending 20-60k on this project may be worth it from a publicity perspective?

Posted by: jimofoz at December 30th, 2019 9:50 AM

Questions for Mathew O' Connor and others involved in Senescent cell research.

Drs. Connor, Frost, and others:

Until real senolytics come along, I am trying a number of natural compounds.

The ones I have in mind are - Berberine(for which I already take), and Fisetin.

I also use Quercetin from time to time.. I am looking for natural enhancers of the p53 gene.
I am also using TA-65 on the front end to lengthen telomeres.

Posted by: Jeffrey Schnitzer at September 2nd, 2022 12:51 PM
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