What the aging field needs

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Changing the narrative – Celine Halioua reveals why the aging field needs to be taught some new tricks.

Celine Halioua is the Founder and CEO of Loyal, a company that works collaboratively with dog owners and the world’s leading aging scientists to develop the first FDA-approved therapies to enhance dogs’ wellbeing and lead to better, longer lives. With two drug candidates poised to enter clinical trials, and an ongoing observational study designed to track specific biomarkers in dogs of different breeds, ages and sizes to better understand why small breed dogs live longer, it’s an exciting time for the company.

Longevity.Technology: Halioua is dedicated to developing medicines for for aging and the diseases of aging; prior to starting Loyal, she was Chief of Staff at The Longevity Fund, an early stage venture capital fund. Halioua holds a Bachelor’s of Neuroscience from The University of Texas at Austin, and was a DPhil student at The University of Oxford studying the economics of curative medicines before dropping out to pursue the independent research and entrepreneurial passion that has now led to Loyal. 

When she drew on her experience recently to write a blog on What the aging field needs, which she summarised on Twitter, covering what the aging fields needs to work on if we are to have the first aging drug approved this decade, we, and her 17,000 other loyal followers, were interested. We caught up with Celine to discuss her op-ed (which follows below) and the motivation for it.

“I think the most controversial opinion I have from an aging standpoint, and something I’m pretty loud about, is that I think we have moved past the time where this ‘immortality,’ ‘1000 year old human,’ even ‘150 year old human’ narrative is helpful to the field,” Celine Halioua told us. “The idea of an aging drug is completely non-controversial – it’s basically a statin for every age related disease – it’s a preventative mechanism for the worst diseases that we have. And that fits perfectly with standard pharma really, but it’s not seen that way.

“We now have a lot of preclinical, research stage, things that have showed efficacy in non-human models, so we need to quickly develop some subset of them and show if they work or not. And this is really a time when you need to have strategic conservatism. There are set boundaries – you have to deal with regulatory agencies, the FDA, insurance payers, pharma, and you have to raise very large sums of money from people who are going to be turned away by these 1,000 year lifespan claims. And so I’m quite loud about that, because I think it’s a trend I see in the aging field where people repeat these things over and over again, and I think it actually pulls back the field.”

Halioua feels there’s an argument to be made – and it’s one with which she agrees – that the audacity of big statements were really critical in the 80s and 90s “when nobody was thinking about this field and nobody was paying attention”.

“But I think we’ve moved past that time,” she says, “so that’s one of the big things that I want to talk about, and a key driver behind the article.”

Taking about longevity and encouraging discussion promotes interest in the field and current research, of course, but as with all opinions, there are assenters and dissenters.

“I think I definitely annoyed some people with the strategic conservatism thing. But debate is good – intelligent, data-based debate on these things is only a positive for the field. I’m 100% okay with being proven wrong on any and all of these points. My thesis on writing and putting stuff out there about aging is, if nothing else, it may incite somebody who has a better opinion or more informed opinion to then counter me, and then that gets published, so it really can’t hurt.”

What the aging field needs

The first aging drug could be approved this decade.

The basic thesis behind the aging field is that we can increase healthspan (quality of life) and lifespan (number of years lived) by developing medicines which specifically treat the ways our bodies age over time. The ability of certain drugs to increase lifespan & healthspan has been demonstrated hundreds of times in model organisms like mice, but to date no drug has ever been approved to explicitly treat aging in humans. Aging drugs, if they live up to the fields’ dreams, could significantly improve quality of life and reduce disease burden and misery for millions of people.

Celine Halioua

The reasons we do not have an approved aging drug today are not due to the science – the biological blockers to a first-generation aging drug have been clear for at least ten years. The primary reasons there are no approved aging drugs today are much more tricky – they are regulatory, societal, structural, and cultural.[a]

For the last years, I’ve been a researcher in academic aging labs, worked in aging-focused venture capital and early-stage aging drug development start-ups, and am now the founder of the aging biotech Loyal. The common theme of my work has been trying to find the highest leverage way to support and accelerate the first aging drug approval.

This is my assessment of what the aging field needs to do if we are to have a reasonable shot at the first aging drug this decade:

1) More teams taking on regulatory risk

TL;DR – aging drugs should be tested for their benefit on all-cause aging, not specific diseases.

For a new drug to be approved for use in a specific disease, you must show that the drug is safe and efficacious in a series of clinical studies.[b] These clinical studies are run with the approval and guidance of the FDA, the federal body that regulates drugs in the United States. You must come to an agreement of what study design and endpoints[c] would support a label claim for your drug’s desired use.

Currently, there is no regulatory path for a drug to have an explicit aging label claim. Therefore, most efforts use ‘proxy diseases’ – classical diseases already recognized by the FDA. Most aging companies use one of two core strategies:

  • Pick a disease they believe will respond to their drug (often a disease unrelated to aging, e.g. a genetic disorder around the pathway), and then use Phase IV/follow-up studies to show an additional aging benefit, and/or
  • Pick a disease that they hypothesize is driven by mechanisms of aging and therefore an aging drug might treat.

Testing your drug on a traditional disease significantly reduces regulatory and some aspects of clinical risk. The market for these diseases is well understood, there are existing insurance codes and standards of care, pre-validated clinical trial designs, and the regulatory path is straightforward. It’s also often a lot cheaper and faster than any plausible aging study.

Unfortunately, testing an aging drug for anything that is not explicitly aging increases the probability of false fails. The question isn’t simply: “Does the drug work?” as it should be; instead, it becomes: “Does the drug work?” x “Does this specific disease respond to this drug?” x “Is the magnitude of benefit clinically relevant for this disease?”.

That’s at least 2/3 ways for the drug to fail that have absolutely nothing to do with the actual question: whether the candidate drug treats and slows aging.

2) More translational aging companies

TL;DR – we don’t need a hundred aging companies working on new drugs – we need companies that know how to run aging studies.

There are very few aging companies. But of those, most are focusing early: identifying new targets and ways of drugging aging. This makes sense – the big bucks in biotech are usually in novel chemical matter (drugs) that you can somewhat prove out and then sell to Big Pharma.[d]

New and better targets are critical to developing the most effective aging drugs. However, there is a bigger beast to slay first: how do you run an aging trial? What are the endpoints? If there is no way to get an aging drug into humans and approved, the quality of your drug simply does not matter.

This question has been postured to death with very little actual execution or even attempts. We need companies to take a drug that is likely to work to some clinically relevant degree and blaze this path. While there is no direct financial upside to pioneering a clinical trial design (both structurally – you must share your trial publicly – plus ethically), there is a company benefit of becoming incredibly competent in efficiently running aging studies.

3) More sustainable business models

TL;DR – to do ambitious things, companies need to be self-sustainable and not be dependent on conservative incumbents for cash infusions.

Most biotech companies, whether they realize it or not at inception, are build-to-buy plays.[d] The core competencies to execute excellent early-stage drug development is diametrically opposed to the competencies necessary to run late-stage clinical studies and to commercialize a drug. It is also incredibly expensive to run late-stage trials and commercialize a drug, and most companies simply cannot raise enough capital.

This is not necessarily a problem for a standard drug for a standard disease. However, the Pharmas are unlikely to be early adopters to the aging thesis, nor be motivated to take on regulatory risk, business model risk, etc. There is also concern that an efficacious aging drug would undercut their existing drug programs.

For an aging drug to make it through to the finish line, the first aging companies will need to have the ability to bring their drugs from idea to commercialization without selling out to Big Pharma. This will require…

4) More investors bullish on aging

TL;DR – developing the first aging drugs will take patient capital.

The aging field needs more investors with a high quality bar, long time horizons, and significant capital resources. The current aging investor landscape is largely ‘pick two’ – lots of money is going to low quality efforts, great companies dampened by short-term capital, and high quality ideas that are underfunded.

Aging isn’t quite de-risked enough yet for broad swathes of investors to feel safe putting significant capital in this area. Unfortunately, in bio the probability of success is highly correlated with the amount of capital in the coffers.

If we want an aging drug this decade, we need multiple well-funded ($100M+) shots on goal. These shots on goal need to be funded even if their first few attempts fail. Patient, rigorous capital is key to breaking through this field.

5) More (strategic) conservatism

TL;DR – aging drugs are not about immortality. They are about a better way to treat some of the most challenging diseases facing humanity.

The longevity field first reached prominence with claims of extremely long human lifespans and even immortality. While attention grabbing, this has set the tone of aging drugs being controversial, debatable, even unethical.

Fundamentally, an aging drug is an all-cause mortality and morbidity drug. Think – statins, but instead of just for the heart, also for neurodegenerative disorders, joint pain, and other aging maladies. This is not controversial.

Additionally, for aging drugs to pass over the many hurdles before market approval, the field needs to strategically match Big Pharma and regulatory conservatism. Aging drugs need to be framed in a way that fits the current frameworks and balances the risk:reward ratio that is of concern to the regulatory agencies; try not to over-hype them. At these levels, change is slow and incremental.

While the ethical debates may be prudent in the future, we are extremely far from these debates being relevant. Inducing them now with irrational rhetoric only hurts the chance of having any aging drugs at all.

6) More new ideas

TL;DR – the aging field uses the same tools over and over, limiting our understanding of aging itself.

Metformin, rapamycin…the aging field plays favorites with drugs. This is for very reasonable reasons! These drugs are rigorously, independently validated by multiple groups; equally validating new drugs is expensive, laborious, and time-intensive (lifespan studies!) [e]

These drugs are great tools for understanding some aspects of aging. But like any tool, they have their limitations. By not expanding our set of aging tools, our understanding of aging itself is limited. We can only see the aging mechanisms and pathways that these drugs specifically affect. It is difficult to tease out mechanisms and biomarkers that are relevant to aging in general versus just the mechanism of a few favorite tools.

7) An interdisciplinary approach

TL;DR – aging is not a separate discipline of biology; it is cross-functional across all the other disciplines.

To develop a drug against ‘aging’ is one of the broadest briefs in biology. The pieces of the puzzle are spread across fields seemingly unrelated to each other. I have purposely hired scientists from non-aging fields – having perspectives of other fields has improved our thinking immensely.

Insular thinking will cause us to miss the crumbs of clues strewn across all of biology.

We also spoke to Celine Halioua about her work in the dog longevity field – read more!

Footnotes

[a] Regulatory – Currently, no regulatory path forward for a drug to have an aging label claim. Societal – Aging has a severe branding problem, which has made the idea of an aging drug controversial. Structural – Aging (preventative) drugs do not fit as well into the United States’ multi-payor insurance & reimbursement system. Cultural – Pharma conservatism not conducive, and investors are still skittish around the idea of aging drugs.
[b] A summary of clinical development can be found here.
[c] Endpoints = the (usually) quantitative markers that your drug is assessed on for therapeutic benefit. For example, the primary endpoint for the COVID vaccine trials was incidence of symptomatic COVID infections in the treatment vs placebo arm.
[d] Most biotech companies end up selling their drug or the company to Big Pharma
[e] Average mouse lifespan is about 2.5 years.

Images courtesy of Celine Halioua
Eleanor Garth
Deputy Editor Now a science and medicine journalist, Eleanor worked as a consultant for university spin-out companies and provided research support at Imperial College London and various London hospitals in a former life.

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