VDP-112 [Assessment] Cyclarity - Novel cyclodextrin molecules for multiple aging-related diseases

One-liner: Cyclarity Therapeutics is an early stage biotechnology company developing computationally designed novel cyclodextrin drug molecules for the extraction of toxic biomolecules that accumulate with age and are implicated in a variety of age-related conditions including cardiovascular disease, macular degeneration, stroke, and liver failure.

Longevity Dealflow WG Team

  • Senior reviewers: 3 scientists, 2 biotech managers, 1 biotech entrepreneur, 1 pharma consultant
  • Shepherd: Paolo Binetti
  • Squad members: Ryan Spangler, Ashish Rajput
  • Sourced by: unsolicited application

Project PI

  • Matthew O’Connor, co-CEO

Simple Summary

Cyclarity Therapeutics (CTx) engineers cyclodextrin (CD) molecules designed to extract toxic biomolecules that accumulate in cells and tissues as a consequence of aging. Our lead compound targets toxic oxidized cholesterol, which is most heavily associated with cardiovascular disease (CVD), but is also implicated in dementia (including Alzheimer’s Disease), liver failure, and macular degeneration. We are also developing a computational platform incorporating artificial intelligence (AI) and machine learning (ML) to design novel CD molecules tailored to any target.


There are likely many toxic biomolecules implicated in aging, but our lead candidate targets possibly the worst, oxidized cholesterol, and more specifically, 7-ketocholesterol (7KC). 7KC accumulates in cells over time as a result of normal biological processes, and contributes to cellular dysfunction [1]. The condition most profoundly implicated with 7KC is atherosclerosis, with high levels found in plaques and cells that promote plaque development [2]. Collectively, atherosclerotic diseases are by far the world’s biggest killer, contributing to 44% of deaths worldwide (2017 WHO and US Dept. of HHS all-cause mortality risk-adjusted data).

Atherosclerotic lesions consist of dead cells, cholesterols, calcium deposits, and macrophages. Initially, macrophages attempt to clean up the burgeoning lesion through ingestion and removal of accumulating detritus. Upon consumption of the 7KC that is commingled with normal cholesterol and other lipids in the lesions, macrophages become choked with lipids and transform into pro-inflammatory and functionally inactive foam cells.


Cyclarity’s approach to addressing toxic biomolecules is to develop CDs, carbohydrates with a truncated conical shape, as active pharmaceutical ingredients (APIs) that bind to these toxins with high affinity and specificity [3]. CDs bind to hydrophobic molecules (such as sterols), thereby conferring solubility to otherwise insoluble molecules. Widely used for industrial and drug delivery applications, CDs have an excellent safety profile: some are GRAS and FDA Inactive Pharmaceutical Ingredient listed, and clinical trials are underway using one CD (Hydroxypropyl-beta-CD, HPBCD) as an API to remove normal cholesterol from children with NPC [4].

To develop our lead candidate (UDP-003), we used a combination of computational and wet-lab science to screen hundreds of theoretical and existing CDs and rationally designed a novel class of CDs with high affinity and specificity for 7KC. Our CDs are engineered dimers in a configuration which optimally encapsulate sterols and are modified with substitutions optimized for 7KC binding [3]. The computational methods used to develop our CDs have formed the basis of our computational platform, which we are developing to design CDs to target additional toxins. We have focused on continued development of UDP-003 for treatment of atherosclerosis and other 7KC-implicated diseases of aging.

Our data shows that UDP-003 has much higher affinity for 7KC compared to monomeric CDs, and that specificity for 7KC over cholesterol is also excellent [3],[5]. We found that UDP-003 extracts 7KC from human atherosclerotic vascular tissue and blood cells. Application of UDP-003 to foam cells reverses the accumulation of lipid droplets and returns them to a macrophage-like morphology as shown by Oil Red O staining (Fig 1A). We also found that when UDP-003 is administered to foam cells, phagocytosis activity is increased to close to normal (Fig 1B). This indicates that administration of UDP-003 returns foam cells to both regular macrophage morphology and phagocytic function.

Pharmacokinetics (PK) studies showed that UDP-003 has a short halflife and high parenteral bioavailability that increased linearly with higher doses. It was found that IP and subcutaneous administration facilitate high bioavailability. The high bioavailability of UDP-003 through subcutaneous administration represents a major advantage, as it shows the viability of a final injectable product.

Non-GLP safety-toxicology experiments have shown that UDP-003 displays acute and repeat dose toxicity only at high doses. GLP ototoxicity has yielded a No Observable Adverse Event Limit (NOAEL) of 650 mg / kg in rats. Our clinical trials plan to test a range of 1-20 mg / kg in humans

CTx is preparing for Phase 1 clinical trials of our lead drug candidate. Good Manufacturing Practice (GMP) manufacturing of KGs of UDP-003 has been completed, and general tox studies under Good Laboratory Practice (GLP) are underway. Going into clinical trials, we are confident that UDP-003 is a solution for the problem of atherosclerosis (and eventually other disease indications), and that our model of designing novel CDs tailored to specific targets represents a new mode of drug design and a new method of combating aging.


Our lead candidate will treat patients with atherosclerosis or at risk, reducing plaque burden and the risk related life-threatening conditions such as cardiovascular, pulmonary, and neurovascular diseases. Coronary Artery Disease is the biggest initial indication we could aim for - and regulatory conditions may be right to request conditional/accelerated approval on the basis of plaque reduction rather than CVD events. This therapeutic also has the potential to treat other conditions related to the accumulation of 7KC and other oxysterols such as Alzheimer’s disease, NAFLD, and COPD. The value of this treatment is thus substantial; below we will focus on the atherosclerosis market.

The financial burden of atherosclerosis is immense, with annual US CVD costs totaling approximately $555B in 2017 and with a projected increase to $1.1T by 2035 [6]. It is projected that the worldwide market for cholesterol mediation drugs to combat atherosclerosis, even with only current non-disease modifying drugs, will reach $37.7B by 2027.

We have two obvious competitors in the field of developing CDs as APIs: CTD Holdings (Cyclo Therapeutics) and Beren Therapeutics. Both are developing formulations of the well-characterized HPBCD. CTD’s primary indication is for the treatment of NPC disease while Beren is rumored to be targeting familial hypercholesterolemia. We have significant advantages over these companies. First, our CDs are ~1000 times more potent than their drugs, which require high doses for efficacy. Second, we have tailored our engineering program to target toxic oxidized cholesterols, while they remain focused solely on bulk cholesterol. Third, we have an IP advantage in that we have patents on new matter.

Pharmaceutical targeting of oxidized cholesterol is attracting the attention of other approaches. Both AstraZeneca and Abcentra are developing monoclonal antibody therapeutics for the inhibition of ox-LDL activity. The development of these validates the importance of targeting ox-LDL and other oxidized lipoproteins as treatments for cardiovascular disease. However, we have major advantages over these competing therapeutics. Cholesterol can be oxidized in cells independent of ox-LDL absorption, meaning that targeting ox-LDL will not eliminate 7KC or reverse foam cell formation. Also, the mechanism of UDP-003 is to extract 7KC from cells rather than to block interaction of particles and cells. Blocking the entry of ox-LDLs into cells can prevent further damage, but cannot reverse it. Finally, UDP-003 has zero immunogenicity contrasted with the competing drugs, which are both monoclonal antibodies.

Repair Biotechnologies and Bitterroot Bio also represent competition in targeting atherosclerosis as an indication. Repair Biotechnologies is developing a cholesterol degrading platform to target cholesterol in atherosclerotic plaques and reduce plaque size. Repair’s approach is elegant and the only clear advantage we have is that we have a much easier regulatory path and therefore despite having started development at about the same time we’re almost ready for clinical trials. Repair’s approach may someday be completely synergistic and complementary to Cyclarity’s approach. Bitterroot Bio is developing a therapeutic to target CD47 which powerfully activates macrophages and may thereby help to clear plaque. The latter could have unforeseen side effects from tampering with a basic cell signaling pathway as has occurred in clinical trials of the same CD47 cancer therapy that has halted clinical trials of essentially the same drug developed by essentially the same group.

All of these approaches are completely different and revolutionary compared to the current standard of care. One or more of us will share in the trillion dollar prize and help save a billion lives in the next 10 years.

Of currently available drug treatments for atherosclerosis, none are disease modifying. Statins and other lipid lowering treatments are good at lowering LDL, but at best only slow atherosclerosis progression. Blood thinners protect against blood clots that can form as a result of atherosclerosis but do nothing to reverse underlying disease. The opportunity, thus, is not only to potentially replace the market for current non-disease modifying drugs, but to significantly reduce the overall economic costs of CVD and to reduce the immense social burden of this condition.

It is likely that there will be a liquidity event for investors in approximately 3 years. Demonstration of reduction in coronary plaque volume in ph2 will be major in terms of value. A licensing or acquisition or IPO at that stage, given the market just for CVD briefly outlined above, would run in the billions of dollars in value.

Relevance to Longevity

We focus on removing toxic biomolecules which accumulate in cells and tissues over time due to biological and physical processes over the course of aging. The mechanism of our lead drug is to remove the target oxysterol, rejuvenate foam cells back into functional macrophages, and reduce the plaque build up effects of atherosclerosis. Our lead molecule is tailored precisely for the oxidized target, it has maximized affinity and is effective in safe dose ranges. This creates a new and superior approach to treat an extremely common disease associated with aging that causes a substantial decrease in lifespan. As oxidized cholesterol accumulation is a basic damage molecule that accumulates with age in many cells/tissues it is implicated in many diseases of aging [1].

IP Roadmap

First Group: Cyclodextrin dimers, compositions thereof, and uses thereof

  • Broad composition claims expected for the useful set of engineered dimers
  • Priority date Jan 2019; First issue Mar 2022
  • National Stage in US, Europe, Canada, China, India, Japan, Australia, Israel
  • Issued patent in the US. Patent filing date: 1/03/2020; US Patent Publication No. 20200216576.

Second Group: Cyclodextrin dimers and uses thereof

  • Coverage of new dimer variants and new dimer types
  • Priority date July 2020
  • US and PCT

Computational Platform (trade secrets):

  • CandymerTM: Cyclodextrin molecular dynamic simulation system
  • Cyclodextrin-Target affinity (Potential of Mean Force) prediction system
  • AI / ML of system

Experimental Plan

The full roadmap, summarized in the figure below, consists of three phases, which are described thereafter.

Completion of GLP Safety Studies

We have begun in vivo GLP studies to ensure that UDP-003 is safe for repeat dose administration in clinical trials. We are preparing a 28-day repeat dose toxicology study in Yucatan swine, as the similarity between the cardiovascular systems of humans and swine can inform safety. This will include a toxicokinetic arm and toxicology assessment. Upon the completion of all GLP studies, the safety of UDP-003 for use in humans will be established and clinical trials can be initiated.

Initiation of Phase 1 Clinical Trials

We are preparing to initiate Ph1 Clinical trials to determine dosing and safety in human patients. This trial will be a traditionally designed SAD/MAD randomized, double-blind, placebo-controlled study to establish safety, PK, and PD parameters in human subjects. Based on recommendations from MHRA, we will be enrolling an arm with atherosclerosis patients in the MAD part of the Ph1 to improve the chances that we obtain patient group-specific safety, PD, and anecdotal efficacy readouts in phase 1 to inform dosing in later phase trials.

Clinical Phase 2 plan and potential exit

Ph2 will seek to link 7KC target engagement data with plaque reduction efficacy data to allow for evaluation of our overall strategy. Very briefly, the plan is to recruit 500 patients who will be randomized into 3 arms (placebo, low-dose, high dose). The course of treatment will be finalized based on Ph1 data, but will likely be delivered over 3 weeks, with weekly analysis of blood, urine, and physiological measurements. Post treatment monitoring will consist of monthly analysis of blood, urine, and physiological measurements.

Successful reduction of coronary plaque would be an enormous value inflection point for the company, which could be worth billions. Exit could could take the form of an acquisition, IPO, or licensing deal for UDP-003.


The budget for the first two phases of the roadmap above, Completion of GLP Safety Studies and Initiation of Phase 1 Clinical Trials, which are the scope of the current round, is the following:

  • Personnel: $900,000
  • Facilities: $100,000
  • Business expenses: $150,000
  • Lab expenses: $100,000
  • Legal: $200,000
  • Chemistry/CMC: $500,000
  • In vivo: $1,000,000
  • Computational: $100,000
  • Regulatory/QA/QC/PM: $300,000

Total: $3,350,000

Financing and VitaDAO funding terms

CTx completed a Series Seed round November 12, 2019, with a total committed cash investment of $3.95M. The round had three institutional investors, and six angels providing small amounts, and was led by Kizoo Technology Capital GmbH.

Cyclarity completed Series Seed II on August 24, 2021 with an additional committed cash investment of $10M. Kizoo TCG led the round. Post-money valuation of ~$28M.

Cyclarity is currently raising funds for a $3-4M Bridge Round. We have over $3M committed for this round. The bridge round funds will be used for final preparations and initiation of Phase 1 clinical trials. Additional funds will need to be raised to complete the Ph1 clinical trial. We will need a total of not more than $12M to complete Ph1 (including the bridge round).

Cyclarity has allocated 100k for the VitaDAO community in the bridge round under a SAFE agreement with a 15% discount for the line items in the budget.



  • Dr. Matthew O’Connor, Co-Chief Executive Officer and Co-founder: Dr. O’Connor was awarded his Master’s degree in neuroscience from Northwestern Medical in 1999 and his Ph.D. in Biochemistry from Baylor College of Medicine in 2005. His postdoctoral research includes work at UC Berkeley on muscle stem cells and aging. He is the former VP of Research at SRF where he oversaw a broad swath of research projects spanning many aspects of rejuvenation and biotechnology from which he authored many papers and patents.

  • Michael Kope, Co-Chief Executive Officer and Co-founder: Mr. Kope helped establish SRF in 2009, and served until 2019 as its founding CEO. He received his J.D. from the University of Michigan in 1990. He has served as the University of Michigan’s Intellectual Property Counsel, Director of Corporate Development for Aviron/Medimmune, Inc., and as CEO and officer of multiple biotech startups.

  • Frank Schuler, Board of Directors: Mr. Schuler is a principal of Kizoo Technology Capital GmbH (Kizoo TCG), our lead investor. Mr. Schuler co-founded Kizoo TCG, led the IPO of WEB.DE, and since then has helped numerous start-ups to grow. As part of the Forever Healthy Group, Kizoo TCG directly supports the creation of start-ups turning research on the root causes of aging into therapies and services for human application.

  • Dr. Noah Rosenberg, Clinical Director: Dr. Rosenberg has deep experience in CV/metabolic drug development and medical affairs at both large (Pfizer, Sanofi, Forest labs) and small (Travere, Esperion) pharmaceutical companies. He has led multiple successful drug submissions and launch teams. Noah completed his B.A., M.D., and residency at The Johns Hopkins University, Drexel University, and Mount Sinai Hospital, respectively.

Key Collaborators

In addition, CTx partners with international experts in computational and synthetic chemistry. We work closely on computational efforts with Professor Ángel Piñeiro and Professor Rebeca Garcia Fandiño of MD.USE Innovative Solutions, the world’s leading specialists in the development of CD-specific simulations. For our synthetic chemistry efforts, we partner with Dr. Milo Malanga, CSO of CarboHyde and an expert in CD synthesis.

Scientific Advisory Board

Cyclarity’s Scientific Advisory Board includes Dr. Lajos Szente, Dr. W. Gray Jerome, and Dr. Philip Lavin. Clinical advisors include world-renowned cardiologists including PK Shaw, Mike Farkou, and Steve Nicholls.

Slide deck

Slide Deck: CyclarityTx-Pitch Deck-v5.31.pdf - Google Drive


  • Targeting one of the largest markets among aging-related disease
  • Unique mechanism of action
  • Strong IP on CoM of completely novel drug class
  • Encouraging preliminary results, superior to competition
  • Very close to clinical trials
  • “Pipeline in a pill” in that UDP-003 applicable to many other conditions such as AMD, NAFLD, Alzheimer’s, COPD, and others
  • Platform for targeting many other toxic biomolecules that accumulate with age


  • Novel modality for cardiovascular disease, although proven for other applications
  • Strong competition from other promising startups
  • Entrenched interests will fight to maintain status quo
  • CVD is a notoriously difficult indication to prove success in and get new approved drugs.


  1. Anderson, A. et al. 7-Ketocholesterol in disease and aging. Redox Biol. 29, 101380 (2020).

  2. Wang Julie C. & Bennett Martin. Aging and Atherosclerosis. Circ. Res. 111, 245–259 (2012).

  3. Anderson, A. M. et al. Cyclodextrin dimers: a versatile approach to optimizing encapsulation and their application to therapeutic extraction of toxic oxysterols. Int. J. Pharm. 120522 (2021).

  4. Malanga, M. et al. “Back to the Future”: A New Look at Hydroxypropyl Beta-Cyclodextrins. J. Pharm. Sci. 105, 2921–2931 (2016).

  5. Anderson, A. et al. Addressing the Complexities of Cyclodextrin-Sterol Affinity Constants: a Multidimensional Characterization Study. Unpublished.

  6. Dunbar, S. B. et al. Projected Costs of Informal Caregiving for Cardiovascular Disease: 2015 to 2035: A Policy Statement From the American Heart Association. Circulation 137, e558–e577 (2018).

Senior Review Digest - Quantitative

Below is the average scores out of 5 per category from 7 reviewers, who all recommended that the project should be advanced for community feedback.

Average Scores

  • Novelty 4.0
  • Feasibility 3.5
  • Relevance 4.5
  • Science Team 3.7
  • Market Advantage 3.9
  • IP Potential 3.8
  • Conviction score 4.1

Senior Review Digest - Qualitative

Reviewer 1
The Cyclarity team possesses extensive expertise in the field of aging and longevity research. At the forefront of their efforts is the lead molecule UDP-003, meticulously designed to address not only atherosclerosis but also a spectrum of other age-associated ailments, including AMD, alzheimer’s, COPD, and more. Noteworthy is the drug’s remarkable propensity for minimizing side effects, underscored by the fact that clinical trials are already in the advanced planning stages. Given the science, team, and future plans of commercialization, it should go to the next funding phase.

Reviewer 2
I would recommend VitaDAO to move forward with the Cyclarity project. The check size is small, and the potential is huge (potentially curative) if they succeed. I trust the team with the ability to test their therapeutic hypothesis.

Reviewer 3
This is a company that is highly likely to succeed, based on both its tech and its team, and is being seen that way by numerous other investors.

Reviewer 4
I’m torn on this project. Unfortunately there is no preclinical data in an animal data to deliver high reason-to-believe. If the role of 7KC on the maintenance of plaques is as significant as is hypothesized by the Cyclarity team, as well as many others, this drug is a great candidate. I’d be more comfortable seeing additional animal data before going into human, but with the expected safety profile of the CDs, it could be worth it to just go ahead.

Reviewer 5
For my area of expertise, my only concern is with the costs associated with this kind of clinical trials. Aside from that, the drug has a great potential, if it can actually be proven that is disease-modifying, given the disease burden associated with cardiovascular diseases.

Reviewer 6
Strong team, creative idea with good relevance to longevity. Significant concerns about lack of efficacy data.

Reviewer 7
My concerns (on its business strategies & science) stay the same, but after the pitch I am confident that the team & VitaDAO members can help the company success.

  • Agree
  • Revisions Requested (Detail in Comments)
  • Disagree
0 voters

Is there a paper or three missing from the presentation about these compounds’ pre-clinical efficacy? All I see in the pitch deck are macrophage cell lines and one experiment with ‘plaque tissue’. Does this treat atherosclerosis in ApoE or LDLR knockout mice? What do their aortas look like compared to controls?

I am not convinced by the ‘rejuvenate macrophages’ claim. Do you have cytokine secretion and/or gene expression data from primary cells to support these claims? Only data with 7KC treatment is shown, how does it fare when foam cells are made with oxLDL?

The data also lack direct comparisons to HPCD and the other cyclodextrins. Are there any data supporting assertions that it does work better than HPCD? (or better than an HPCD dimer?) Or is it all theoretical?


We have performed extensive in vivo safety and pharmacology, which has been our main focus in vivo as that is what is required to initiate clinical trials (the FDA has no interest in such “efficacy” data). I am not a big fan of the mouse models of atherosclerosis including the two that you mentioned (eg to my mind, based on the proposed mechanism of action, this should not work in ApoE ko mice, b/c they cannot really perform reverse cholesterol transport), so we are in the process of doing some work in some improved models that we hope to be able to show data on in the not too distant future, and I would include that project on the list of things that we will be able to report back on before the end of this budget period. There is this paper from the Latz group, showing megadoses of a much less potent cyclodextrin doing what you would like to see in ApoE ko mice. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming - PMC

We have attempted to replicate this 3 times with our drug. In 2 of the 3 experiments we showed similar positive results. In a 3rd it was negative.

re: oxLDL vs pure 7KC foaming and rescue: yes, we had done this in mouse and human macrophages using both oxLDL and 7KC with nearly identical results across the board.

Macrophage cytokine / gene expression: yes, we are working on a great story there. It’s not finished yet, but we’ve done a lot with gene expression and we have a lot of good data pro-inflammatory / stress genes being activated in the foam cells and then rescued by our drug. We plan to publish this story in preprint in the next few months and then in a peer reviewed journal next year.

We have compared our drug to HPbCD in many, but not all assays. Our drug is about 100x more potent than HPbCD. Which is good because the NPC patients who get HPbCD infusions (in clinical trials) have to spend about 6 hrs getting an infusion while ours will be a quick in and out.

We do have a lengthy diligence package with reports of all completed, but unpublished, in vivo and in vitro studies and other details available under NDA.

Thanks for the well-informed questions!



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