The Cambrian Biopharma Approach to Obtain Regulatory Approval of Drugs to Treat Aging
The approach outlined here by the Cambrian Biopharma principals isn't exactly a secret: at least the first part of the process is exactly the playbook for nearly every company working on interventions that target the mechanisms of aging. Since there is no established regulatory path to treat aging as a medical condition, companies must seek approval to treat a specific age-related condition. They pick the best choice of the scores that could be treated by slowing or reversing one or more mechanisms of aging. Most groups stop the future planning at that point, as the likely next step following regulatory approval will be widespread off-label use for any therapy that proves effective - and US regulators don't like companies talking about off-label use.
The interesting part of the Cambrian Biopharma plan is how to dovetail existing work on persuading regulators to accept a trial for aging, such as the TAME trial design, with the necessary first steps in gaining approval for the treatment of a single age-related condition. As the longevity industry moves forward, and more approaches reach the point of clinical trials, this sort of open discussion about how to bring the regulators into line with reality will be increasingly necessary. Working within the system like this is one approach. There is also an energetic faction that feels that regulatory arbitrage and medical tourism are more viable approaches, moving treatment to countries with less restrictive and less costly regulatory regimes in order to force change at the FDA through competition.
The Secret Cambrian Bio Master Plan to Build Drugs to Treat Aging (just between you and me)
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 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.
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 or 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.
I went on a rant about this a few days ago, arguing for the approach of seeking approval for established diseases first, but now I'm reconsidering.
Is the FDA approval process for preventative medicine harder or different than it is for pathological diseases?
How hard will it be to get approved for more general things, such as regenerating the thymus, or removing crosslinks from arteries, etc... things that will prevent diseases, but might not seem to have a huge effect right away.
Well, statins are approved, It isn't?
The risk with gero-protectors (Metformin, Rapa, or novel) I fear is that you have to hit the mark perfectly against your "multi-morbidity" basket
And it may be tough to craft the perfect gero-protector strategy, as evidenced by the on-going (and conflicting) Metformin trial data rolling in - https://diabetesjournals.org/care/article/44/12/2775/138471/Effect-of-Metformin-and-Lifestyle-Interventions-on?fbclid=IwAR00EdbvnZAFyoddnwdcdhpM9ivAIDbXA6YjkMz31Bq-bvuQzcQSUW7njiQ
If you don't get things perfect, even if the FDA grants you leeway on "aging claims" at some future date, the claim could end up resembling something more akin tot the old Cheerios health claims - (i.e.....maybe beneficial in X, but not if you have Y, or if you are over 75 with Z, etc. etc....) which helps no-one and ends up a very expensive exercise in drug development...
For now you just get it approved with wider and wider indications until nearly everybody it is approved for.
For some indications there is safety + surrogate markers is enough for approval. In other indications you have to show >15% reduction in clinical endpoints + safety.
Thing is for the QALY numbers to get reimbursements from payers you are going to need the big outcomes studies anyway.
What we want is to show drugs that actually reduce total health spending. (by pushing out or stopping hospitalizations). So then with the pricing it is actually saving insurers money by widely prescribing it.
To evergreen the patents then you do the clinical trials for follow on additive drugs, only with combos of your own drugs.
Eg.. with Entresto Novartis took its drug Valsartan and added a Neprilysin inhibitor Sacubitril. The study showed I think a 16% reduction in hard endpoints versus the standard of care which is Enalapril in heart failure with reduced ejection fraction.
While other angiotensin receptor blockers than Valsartan might work with Sacubitril to produce similar outcomes that is an unknown.
This should allow evergreening into the mid-2030's, of course scam generics companies are suing, without regard for how Novartis needs this cash flow to do more research and clinical trials. So the patent system needs to be made way stronger and the patents last a lot longer, if the companies are like Novartis and doing a ton of more clinical trials on drugs.