The Secret Cambrian Bio Master Plan to Build Drugs to Treat Aging (just between you and me)
January 6, 2022
Background: Cambrian Bio, which I started in 2019 with my co-founder Christian Angermayer, recently announced that we raised $100M from a fantastic group of investors in a Series C round, bringing our funding to around $160M in the last two years. Over 100 scientists, company builders, and drug developers are working together to create the first medicines to slow human aging.
If you ask a doctor what a healthy 60-year-old should do to optimize their health, the only answer well-supported by clinical data today is "diet and exercise." I'm a big fan of good diet and exercise, but even a vegan yogi has less than a 10% chance of making it to their 100th birthday. Medicine can do better. The last decade has seen our understanding of how and why we age expand dramatically. It's time to start putting that knowledge to use to help people everywhere live healthier longer.
Our mission at Cambrian is to create medicines that keep people healthy instead of treating symptoms after they get sick: intervening before a person becomes a patient.
To make this mission a reality, Cambrian is currently developing more than 15 novel therapies (aka drugs) that repair key types of molecular or cellular damage that gradually weaken and age our bodies. By targeting these causes of aging, each of our new medicines has the potential to extend human healthspan, the years of life spent in good health.
Despite the enormous benefits to individuals and society from medicines that could keep people healthier for longer, the development of geroprotectors (aka drugs that prevent age-related decline) accounts for a tiny fraction (less than 1%) of research dollars. The most common reason cited for this under-investment is that “aging” is not a disease, therefore you can’t run a trial to “slow aging.”
This simplistic statement misses the mark in a few ways. The real challenges we need to overcome are more nuanced. They are: (1) multi-disease prevention (i.e., “aging”) trials are risky, expensive, and slow; and (2) we don’t have the biomarker needed to run cost-effective prevention trials in healthy people.
Cambrian’s strategy tackles both of these key challenges with what I call our ‘Secret Master Plan’. Our plan has three stages: get approval for newly developed geroprotectors as treatments for existing diseases causing acute suffering to patients today. Then, when it’s clear these drugs are safe, effective, and valuable, do the large and expensive trials to show that these medicines slow aging in at-risk (often older) people. Finally, we will use the huge amounts of data gathered from rigorous and controlled clinical trials to approve geroprotectors using a surrogate biomarker of multi-morbidity risk (more on this in a bit) to help people in good health stay that way.
Longevity outsiders criticize any preventative medicine approaches because the clinical trials are long and expensive. Longevity insiders criticize our approach of starting with currently recognized diseases because they want to run aging studies now. Both of them are wrong. Prevention studies are both feasible and worth doing, but they can only start once the safety and commercial value of a drug has been established. Here’s how the Master Plan will work.
Stage 1. Show that new geroprotective drugs are safe and effective at treating existing diseases.
Cambrian is starting by applying breakthroughs in our understanding of what causes us to age and decline to make new drugs that treat multiple diseases.
Each new Cambrian medicine will undergo clinical trials in a well-recognized indication (a disease or condition) where patients need better treatments. Regulators, doctors, and patients want to get these new medicines approved quickly to give suffering people better quality of life. It turns out that if a drug can improve one or more of the fundamental biological processes that break down as we age, we can usually find at least one disease that is caused by the same biological process going haywire. Once we identify this disease, we test whether our geroprotector can serve as a treatment for those patients. Clinical trials for these indications can be small and focused which makes it much faster and cheaper for us to demonstrate safety and efficacy with our new drugs. We also get to help people suffering with debilitating and often neglected conditions. We love a win/win situation.
Because disease trials are the first “step” on the path of a medicine to becoming an approved multi-disease preventative, we call it a “stepping stone indication.” The stepping stone indications targeted by our medicines are each multi-billion dollar per year markets. That’s why a drug that demonstrated efficacy in clinical trials is worth billions. For most biotech and pharma companies, this is their entire goal – make a better treatment for an existing disease – but for us this is only the first step.
After achieving a few stepping stones, we will be on solid footing (both scientific and financial) to jump into the more challenging world of prevention.
Stage 2. Show that geroprotectors prevent disease in “at risk” people.
Once we show that a drug is safe, effective and that it targets a specific cause of aging in the stepping stone trials, we can start using our understanding of the causes of aging to prevent diseases before people get sick.
To see an effect of a geroprotective drug in a prevention clinical trial, some people in the placebo arm of a clinical trial must get sick or die while those in the experimental arm of the trial stay healthy. The healthier the people in the trial are, the more people need to be in the trial and the longer it needs to run. Trial size and duration are the two leading drivers of clinical trial costs which means that preventative trials in healthy people must be large, long, and very expensive.
Because a geroprotection study of healthy people in middle age would take decades, our first preventative studies will involve older people at high risk for developing the major diseases of aging. A well-designed trial will deliver a clear yes/no answer on whether a drug reduces risk of multiple diseases in 3 to 5 years. Still a long time, but worth it to show that a geroprotector can extend healthspan in humans.
Philanthropically funded clinical trials are already contemplating this approach, most notably the TAME Trial which proposes to use metformin (an off-patent diabetes medicine that extends healthspan in mice) in elderly individuals to prevent them from developing new morbidities. The bar for new drugs still under patent will be higher than for old drugs like metformin, but new drugs intentionally designed to maximize longevity effects and increase safety will work much better than the field’s first coincidental discoveries like metformin and rapamycin.
A multi-disease preventative taken by at-risk elderly people would be the best-selling drug of all time. In 2030, a drug approved only for people 75 and older would have a market size of over $30 billion per year even if that drug costs less than $1,000 annually (way cheaper than most other drugs and less than a cup of coffee per day in New York). The impact of such a drug would be priceless.
Stage 3. Use a biomarker surrogate endpoint to approve geroprotectors for everyone.
Showing that a drug works to slow aging in an elderly population is an excellent milestone, but geroprotectors will work best if we treat healthy people before they show any symptoms of aging. This hypothesis is supported by animal studies of geroprotectors, where there are diminishing returns on both lifespan and healthspan gains the later an animal is started on preventative treatment.
To approve geroprotectors for younger, healthier people, there must be a clear way of determining in a randomized, placebo controlled trial that the geroprotector is helping, even if people that are getting the placebo aren’t dying or getting sick in large numbers. For this, we need to measure something about the person that predicts whether they will get sick. We call this a surrogate biomarker.
For regulators to accept a biomarker as a surrogate endpoint it must meet three criteria:
- Biomarker predicts morbidity and mortality in large datasets (we have more than a dozen ‘biological clocks’ that do this),
- Biomarker is improved by drug treatment in placebo controlled clinical trials (we will get the data from both Stages 1 and 2), and
- Whenever the biomarker is improved by a geroprotector in a trial, the risk of illness goes down (we will get the data from Stage 2).
To do this, we are collecting data for candidate biomarkers in all of Cambrian’s trials in both Stage 1 and 2 described above. We also launched a data sharing collective with other nonprofit and for-profit leaders in the field to unite the industry around these goals.
Once a validated surrogate endpoint for multi-morbidity risk exists, it will be used to run short (1 to 3 year) prevention trials in healthy adults, and drugs could be approved based on their ability to safely improve that biomarker. This is the endgame of the emerging longevity biotech field, and the dream we have for every new medicine that we guide through drug discovery and into its first clinical trials.
Conclusion. Something old is young again.
This framework will allow Cambrian to test and approve multiple new medicines that proactively treat the molecular and cellular changes underlying the debilitating effects of aging. Much of this will be done for the first time – the medicines will be new, the type of damage they are treating is new, the biomarker is new, and the idea of building a large multi-mechanism prevention framework has not been seen in medicine since the widespread adoption of vaccines.
The good news is that the regulatory path that geroprotectors will follow is not new. Every major drug regulator including the US FDA has already approved preventative drugs. In fact, with a few details altered, the schema I describe here could be a history of the approval of cholesterol-reducing HMG-CoA Reductase Inhibitors (better known as statins with brand names like Crestor and Lipitor, the best-selling drug of all time).
After their discovery, statins were first tested and approved to treat a rare acute childhood disease: familial hypercholesterolemia (Stage 1). Once the drug was proven safe and effective at lowering cholesterol, trials were run to show the drug could reduce mortality in people at high risk for getting a heart attack (Stage 2). Through these trials, the data showed that LDL cholesterol was a surrogate biomarker, so studies for heart disease prevention that focused just on lowering cholesterol were run in younger, healthier people (Stage 3). One could even argue that statins are the first geroprotective drugs, although they reduce morbidity and mortality from just heart disease, instead of many diseases of aging at once.
To accomplish Cambrian’s mission, we don’t have to reinvent the wheel, but the result – a suite of preventative therapies that can keep people healthy for years or even decades longer – promises to be one hell of a new car.
So, in short, the master plan is:
Create drugs that target the causes of aging and show they work to treat acute diseases,
Use these safe effective drugs to reduce risk of death and illness in older people,
Get those drugs approved for everyone using data from earlier trials.
Don't tell anyone.