0xAD1e…dBb8

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

Voting ended almost 2 years agoSucceeded

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. Their 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. They are also developing a computational platform incorporating artificial intelligence (AI) and machine learning (ML) to design novel CD molecules tailored to any target.

Problem

Their lead candidate targets possibly the worst of many toxic biomolecules implicated in aging, 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 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.

Solution

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 their lead candidate (UDP-003), they 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. Their CDs are engineered dimers in a configuration which optimally encapsulate sterols and are modified with substitutions optimized for 7KC binding [3]. With the same computational platform they are also designing CDs to target additional toxins.

Their 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]. They 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). They 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. Their clinical trials plan to test a range of 1-20 mg / kg in humans

CTx is preparing for Phase 1 clinical trials of their 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.

Opportunity

Their lead candidate will treat patients with atherosclerosis or at risk, reducing plaque burden and the risk related life-threatening conditions such as CVD, pulmonary, and neurovascular diseases. Coronary Artery Disease is the biggest initial indication they 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. 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.

They 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. Cyclarity has significant advantages over these companies. First, their CDs are ~1000 times more potent than their drugs, which require high doses for efficacy. Second, they have tailored their engineering program to target toxic oxidized cholesterols, while they remain focused solely on bulk cholesterol. Third, they have an IP advantage in that they 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 CVD. However, Cyclarity has 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. Repair Biotechnologies, a company already positively assessed by VitaDAO, 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 Cyclarity has is a much easier regulatory path and therefore, despite having started development at about the same time, is almost ready for clinical trials. Repair’s approach may someday be 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 these companies 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.

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

Cyclarity focuses 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 their lead drug is to remove the target oxysterol, rejuvenate foam cells back into functional macrophages, and reduce the plaque build up effects of atherosclerosis. 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

They have begun in vivo GLP studies to ensure that UDP-003 is safe for repeat dose administration in clinical trials. They 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

They 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, they will be enrolling an arm with atherosclerosis patients in the MAD part of the Ph1 to improve the chances that they 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 their 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.

Budget

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

Total: $3.35M

Financing and VitaDAO funding terms

CTx completed a Series Seed round in 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 in 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. They 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 be raised to complete the Ph1 clinical trial. They 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.

Team

Leadership

Dr. Matthew O'Connor, Co-Chief Executive Officer and Co-founder: Dr. O'Connor holds a MS in neuroscience from Northwestern Medical in 1999 and a 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), their 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 longevity start-ups.
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. They 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 their synthetic chemistry efforts, they 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

Highlights

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

Risks

Novel modality for CVD, 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.