An Update on Progress Towards Treating Atherosclerosis at Cyclarity

Today I'll point out an interview with one of the Cyclarity Therapeutics founders, illustrative of the degree to which biotech companies are at the mercy of regulators once they arrive at the clinical stage of development. Cyclarity, formerly Underdog Pharmaceuticals, is a spin-out from the SENS Research Foundation, an organization that aims to clear roadblocks in the translational research needed for the production of rejuvenation therapies. The program that led to Cyclarity was focused on finding a way to clear 7-ketocholesterol from the body. 7-ketocholesterol is a form of oxidized cholesterol, created as a result of oxidative stress, and is toxic to cells. Oxidative stress rises with age, and is associated with age-related chronic inflammation, and thus a growing presence of 7-ketocholesterol begins to cause harm in the aging body.

The advance in capabilities developed by SENS Research Foundation and now Cyclarity is to alter cholesterol-binding cyclodextrin molecules to be selective for 7-ketocholesterol while leaving ordinary cholesterol alone. The company is targeting atherosclerosis, hoping to prove that clearance of 7-ketocholesterol can improve on the modest slowing of the condition produced by statin drugs. 7-ketocholesterol is thought to be relevant to the growth of atherosclerotic lesions, acting to impair the macrophages responsible for clearing excess cholesterol from blood vessel walls.

It is clearly the case that in cell culture experiments it requires less 7-ketocholesterol than cholesterol to overwhelm macrophages and cause them to become foam cells or die. The challenge for animal studies is the lack of appropriate animal models of atherosclerosis, ones that exhibit both appropriate levels of 7-ketocholesterol in addition to the development of atherosclerotic lesions. Thus Cyclarity is carrying forward into human trials as the first big proof of concept experiment beyond cells and ex vivo tissue sections.

Solving Atherosclerosis: The Small but Mighty Molecule

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. 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.

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.

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.

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. Steve Nichols, 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 or the third part of our Phase 1 trials. 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.

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.

So 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.

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