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Solving Atherosclerosis: The Small but Mighty Molecule

Cyclarity’s Dr. Matthew O’Connor talks about ending atherosclerosis.

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Matthew O'Connor InterviewMatthew O'Connor Interview

Cyclarity Therapeutics is developing an affordable, plaque-busting small molecule that may be the cure for the world’s number one killer: cardiovascular disease. With human trials planned for this year, we decided that it was time to catch up with Cyclarity and its CEO of Scientific Affairs, Dr. Matthew O’Connor, to see how things were going.

Matthew O’Connor, Oki as he is known to many people in our field, is a biologist. He has a PhD in biochemistry, and he went into science to study aging. He was the Vice President of Research at the SENS Research Foundation for nine years before leaving to form the spinout company Underdog Pharmaceuticals, now called Cyclarity Therapeutics, a few years ago.

Its lead cyclodextrin drug candidate, UDP-003, targets 7-ketocholesterol, an oxidized form of cholesterol that accumulates in cells and tissues with age. Atherosclerosis is the buildup of plaque inside of your arteries, which is formed by the accumulation of this oxidized cholesterol.

The new candidate small molecule drug enters cells and tissues and even penetrates the plaque to grab hold of the oxidized cholesterol, pull it out, and take it away to be safely excreted.

During the last interview we did a year or so ago, Cyclarity was preparing to enter clinical trials here in the UK. You mentioned that there were two broad categories of things that you had to do, which were the safety testing and the manufacturing process. How is it going with those two things?

They’re going great. We finished the manufacturing process for the human quality drug material in what’s called the Current Good Manufacturing Practice. This human-grade material is packaged and in sterile single use vials ready for patients and volunteers.

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We are still finishing the safety testing because we changed the formulation slightly along the road. So there’s some additional, confirmatory tests that we need to do before we can get it into people. There’s a lot of rules and regulations around putting new drugs into people, and so there’s just a few more hoops that we need to jump through that we’re finishing up in the next month or so.

Touching upon the manufacturing side, as you are well aware from your many years of working in this field, one of the big concerns of the community is accessibility. One of the traditional problems with, for example, gene therapies with viral vectors, et cetera, is that they are very expensive. Is what you’re developing something that could be built at scale and therefore is more likely to be accessible?

Yes, while our drug isn’t as cheap to manufacture as drugs like aspirin or statins, it’s a lot cheaper than biologics like therapeutic antibodies or gene therapies, and we’ve built our drug manufacturing process to be scalable. We’ve already scaled that up compared to when we started out. A few years ago, we were only making a couple hundred milligrams of our drug at a time, and now we are making multiple kilograms.

Our process is scalable to dozens or hundreds of kilograms at a time, and it’ll get cheaper as we go. At this point, I don’t think it’ll ever be dirt cheap, like pennies per dose, but it should be affordable to anyone and everyone who needs it.

Pennies are great, but of course those sorts of drugs have been in circulation for decades and are generics by now, making them very cheap. One of the main concerns is accessibility for people; that sounds positive.

When we talked last time, you were poised to go into human clinical trials in Cambridge, UK, working with the Medicines and Healthcare products Regulatory Agency (MHRA). I understand the situation a year on has changed, and you’ve decided to launch in another location, can you tell us more?

We’re continuing to engage with the MHRA. In fact, we have another scientific advice meeting in two weeks that we’ll be holding virtually. We’re excited to be working with the MHRA and hopefully doing part of our Phase 2 clinical trial in the UK.

To remind your readers, we were one of the first recipients of the UK’s ILAP program, the innovative licensing and access pathway, and that’s what really brought us to the UK. In addition to the good environment there, lots of collaborators, lots of innovation happening, especially in the imaging field in the UK.

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The bad thing is that post Brexit, it seems that the MHRA has gotten a bit backlogged and isn’t able to keep up with our current demands on their time. It takes too long to get meetings and responses to applications currently. We’ve had to take our first human clinical trial to Australia, where it’s a faster, more streamlined, and cheaper process.

We are really excited to be working with some great people there. Stephen Nicholls, a world-renowned cardiologist, who we brought on as an advisor, has really helped pave the way and show us the ropes of how to navigate the system and get things going really fast in Australia. We think we’ll be able to efficiently get our trial done there.

This will be a Phase 1 trial, the safety phase, right?

Yeah, we are going to have 12 patients in the second part of our Phase 1 trial. That’s to make sure that it will be safe for patients, but it’s also going to give us a chance to look at those patients and see if their arterial disease and other health factors improve. That will help us with the design of the Phase 2 trial.

The Phase 2 trial will take longer because we have to follow up with patients a year later. That’ll be a bit of a longer process, but we do hope to observe those patients and see if they start seeing some benefits.

We are not talking about a great deal of time in the grand scheme of things, and I remember that you saying it has the potential to reduce the incidence of strokes and heart attacks potentially by 70 percent or higher. Is that right?

What our drug is designed to do is to help clear out the arteries, and that will improve blood flow. Like 70-80 percent of all heart attacks are caused by blockages in the arteries. Since we’re going to clear out the arteries, that should help that 70-80 percent of the population with heart disease that would otherwise have a heart attack.

That should be similar for strokes and actually similar with lung disease. It’s not something that we’re looking at right now, but the vast majority of lung failure, chronic obstructive pulmonary disease, is attributable to atherosclerosis, the blocking of the arteries.

Those are things that sound different, like having a stroke, a problem with your brain, having a heart attack, and lung failure, but they actually have related root causes and we think that in time, we’ll be able to address all of those issues with our drug.

Wow, who knew you could treat multiple age-related diseases at once by targeting the root causes of aging, right?

Obviously we knew, but it bears repeating. When you’re talking about the root causes of diseases, aging is by far the greatest contributor to cardiovascular disease and to dementia because you’re talking about the same aging process that happens in your blood vessels and your heart and in your brain. Fundamentally it’s the same molecules that are at play.

In the case of our drug, it’s cholesterol being damaged by free radicals. You have cholesterol everywhere in your body, anywhere, every single cell in your body has cholesterol in it. Anywhere that a cholesterol molecule gets hit by an oxygen free radical, you’re going to get something that our drug is going to target.

That’s why it’s not surprising when you hear these claims that a drug like ours, targeting a form of cholesterol, or a drug targeting mitochondria is going to help things in completely unrelated tissues.

The old way of thinking is that disease is one tissue or organ at a time, and you have a specialist whose focus is on bone, or muscle, or on the heart, or on the brain, and they don’t pay much attention to anything else. When you approach disease from the perspective of aging, you’re getting at root causes and you’re affecting multiple systems at the same time.

Yes, rather than play the modern medicine game of whack-a-mole, where a symptom pops up and you knock it down, then another one pops up, you do the same again, and repeat over and over, because that’s a game of diminishing returns. The sooner we can move from sick care to healthcare, the better. On that note, what has been the most challenging aspect of getting things to the clinic?

It’s time consuming and expensive to build new therapies. We discussed the scaling process before, which took a lot of time, a lot of money. The safety testing process is time consuming and expensive, but some of these things just take a little bit of time and money, and our field is maturing rapidly.

We have so many more companies like ours entering the biotech space, compared to ten years ago, when things were overwhelmingly at the basic research stage. Ten years before that, it was more academic, observational studies of what aging is.

A decade ago, it was “how can we fix different aspects of aging to address disease?” and now it’s “how can we apply what we’ve been learning for the past few decades to the human condition?” Things are moving along, and things are changing. That said, trying to get therapies into humans is a whole other level of expense, time, and all that.

The aging and rejuvenation biotechnology field has really matured, and there’s so many more investors now than there were just five years ago, let alone ten years ago, which is fantastic. But growing that pool of investors, or building bridges and alliances with more traditional biotech investors and big pharma, is, I think, a big challenge. It’s one that a lot of us at the clinical stage are struggling with now that we’re going to need to raise tens and maybe hundreds of millions of dollars to get this stuff through clinical trials and to market.

I can well imagine, and, as you say, there is a lot more interest. There’s a lot more money coming into the field compared to a decade ago. What do you think is now the biggest sort of barrier to progress for the field?

Well, I think it’s still money, but it’s money at a different stage of the game. For one thing, funding for the earlier preclinical research is a lot more plentiful than it was previously for companies, which is great.

That’s created an amazing ecosystem of longevity biotechnology companies, and there will be a lot of companies now, like us, translating the results from preclinical to clinical work, so we still need the money to grow with us and follow us into the clinic.

That’s one challenge. I think another challenge is in the regulatory realm, because if you come in and you say, “I have an anti-aging therapy”, it’s still tricky to figure out how to design a clinical trial around that.

What may be more practical right now is picking a specific measurable aspect of disease or aging, which I think we don’t really need to distinguish that much between, and asking “How are we going to measure this? How are we going to follow this? How are we going to demonstrate to the regulators that this is an indication that they can sink their teeth into, evaluate, and then approve?” How we are going to convince the regulators that a particular therapy is worthy of being approved for treatment is still a challenge.

I think there’s good news and bad news. I think there’s plenty of room to move forward even without any new definitions of aging as a target or treating aging itself as a therapy. I think it’s actually more important to change the minds of the people developing drugs, as we’ve been doing, by getting in there and doing it ourselves, but also getting other people who would normally be doing something a little more traditionally pharmaceutical to start thinking about it from the aging perspective and getting scientists, doctors, and regulators to be thinking in that context too.

When it comes down to picking an indication, there’s so many to choose from, because most of the major diseases right now are diseases of aging, so I don’t think people should get discouraged by saying, “Oh no, the bad regulators won’t recognize aging as a disease, so we can’t get anti-aging therapies into clinical trials”. Because you can, you just need to pick one aspect of aging to focus on and measure aspects of aging in things like heart disease, dementia, lung function, and muscle function.

Sarcopenia is muscle aging, and it is a recognized disease indication. You just need to put a name on an aspect of aging that you can specifically track and measure. You just need to be strategic about it, and if you can get your drug approved for one thing, you can then start opening it up to treat other, related conditions.

Right, so off-label use for other age-related diseases and conditions which share the same mechanisms and root causes. That makes sense.

Yes, but that said, I think there’s some work to be done in terms of pushing regulators to recognize biomarkers of disease and aging, which like I was saying earlier, are not fundamentally different from each other as things that can and should be measured in Phase 3 clinical trials.

We should be able to at least get conditional, or in some countries what’s known as accelerated or adaptive, approval for drugs. Then, once it’s available for some time, you can start showing things like a reduction in hospitalizations or even increased lifespan.

I think maybe your audience will be surprised to hear that increased lifespan is an entirely acceptable endpoint for a clinical trial, because if you can show people living longer lives, your drug will get approved.

I don’t think it’s a great endpoint for a short, concise trial, though, because people live a long time, so your clinical trial is going to run for a needlessly long time in order for you to prove that. If we can convince the regulators to be a little bit patient and let us get into the public with a convincing amount of data, and even more data on these longer-term endpoints, I think we will be in better shape. There are avenues for doing that. I think that in a lot of cases, we just need to convince the regulators to broaden those policies and let us use them.

Ironically, the more successful a therapy that increased lifespan was, the longer you’d have to wait for it to be approved under the current system, right?

That’s why I think that should be part of Phase 4, which is the post-approval data collection process, while we get convincing biomarker data in Phase 3 to get the approval or temporary approval on.

There’s always a case to be made for disease modification as an endpoint, which the FDA should be okay with, right?

Yes, but there’s a catch. For example, if I have a patient with an artery that’s 70 percent blocked with plaque and then we do our drug treatment and we reduce it to 20 percent, that would be amazing, right?

That would be a huge breakthrough, that would be a tremendous improvement in the health and state of the artery. That said, I don’t know of any country in the world that according to current policies would approve that drug on the basis of what I just said. According to the current standards, you need to demonstrate a reduction in heart attacks or strokes or deaths.

That is the difference that I’m talking about, that we need to push for approval on the basis of something measurable that seems like it obviously should have a beneficial effect, like a reduction in plaque, which will result in increased blood flow, which should result eventually in fewer heart attacks and strokes.

It’s really kind of morbid if you think about it. Being asked to sit and wait for people to have heart attacks and strokes to see if your treatment group is having them less frequently than your control group is having them, right?

Now, you still want to gather that data and see that people who are able or who choose to take your therapy have fewer heart attacks and strokes than people who aren’t taking your drug. That data should be gathered over time, but should we be forced to wait for people to get access to potentially life saving drugs until you can prove that? I really want to push on that right now.

Yes, some changes are clearly needed in the regulatory system. What else is going on at Cyclarity?

Yeah, so we’re excited to be starting Phase 1 soon in Australia and we’re continuing to test our drug for other disease indications. We’re collaborating with other groups to test our drug in other areas and are very interested in collaborations with other groups.

If there’s academic groups or other companies who have model systems for a disease that our drug might be effective in, we are open to collaborating. For example, we’re looking at liver disease. Basically liver aging when you get liver failure caused by the accumulation of lipids and potentially oxidized lipids like we’re interested in.

It would be great to have experts in different areas ask me for samples of our drug and get a collaboration going. To test and see what works and if there’s other applications for our drug that we’re not yet pursuing.

That’s something we’re looking at, and then we’re also developing new drugs. We’ve got a platform to build and design new drugs to grab toxic biomolecules that accumulate with age in various cells and tissues and remove them and hopefully rejuvenate them.

I don’t have anything to report, yet, but we have a lot going on. We have five papers that we wrote in the past year, and two of them have been published, and three more of them should be coming out soon.

We’ve got a lot of cool stuff in the works, and a lot of that has been in tool building. We’ve built an unparalleled computational chemistry platform for building cyclic carbohydrates that we have engineered to grab onto things and pull the junk out of tissues. We’re also doing a lot of computational modeling and using AI and machine learning algorithms.

Instead of us manually pointing and saying, do this, do that, we are training the systems to do it themselves. There’s been a lot of progress on the platform side of the company that gets overshadowed by the progress we’ve made with our lead drug going into the clinic. We hope that we’re going to have perhaps ten new drugs in the coming years in our development pipeline.

That sounds very interesting, sucking the junk out of tissues. Could that include things like lipofuscin or perhaps advanced glycation end products (AGEs)?

Yes, I would say lipofuscin but in a broader sense than the 1970s definition of it. I would call our first drug target a component of lipofuscin; it does accumulate in lysosomes, and it is molecular junk.

There are other things like that, other toxic lipids that we can target and environmental toxins like metals, air pollutants, and microplastics that are accumulating.

That would be great to have that technology to deal with environmental disasters and could be very useful for removing pollutants from humans and or wildlife. It could help with disasters like the nuclear accident that happened in the 80s in Chornobyl, Ukraine or the Fukushima, Japan nuclear accident.

As you say, that’s been overshadowed, but that’s very exciting because that’s something that stems from a repair based engineering approach to the root causes of aging. Again, it’s back to not just treating one disease at a time, instead targeting the foundational causes of aging to treat many conditions at once.

Any final thoughts for our readers that you would like to share?

Yes, keep track of us by following us on Cyclarity Twitter and Cyclarity Facebook, check out the Cyclarity website, and sign up for updates and get in touch if you want to collaborate or are an investor.

You heard it straight from the horse’s mouth. Get in touch if you’re interested in collaborating or investing, and hopefully next time we talk, the clinical trials will be underway. Thanks for joining us today Oki, and best of luck to the Cyclarity team!

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.