Longevity Innovations vs. Moonshots

The last few months have seen a continuing explosion of worldwide interest in the longevity space, particularly punctuated by the quadruple announcement of large financing rounds of Altos Labs ($3B), RetroBio ($180M), NewLimit ($100M), and Life Biosciences ($82M). These four companies have multiple preclinical programs, but are united by an interest in a moonshot technology called Partial Reprogramming, which has demonstrated some very exciting ^[1,2] and some disappointing ^[3] results in the past few years.

I have heard multiple times in the last few months scientists, investors, and observers claim that Partial Reprogramming is the most exciting path to extending human healthspan ^[4]. I disagree, which is why today I want to discuss this interesting meta-narrative around longevity biotech, namely, whether the biggest impact on longevity will come from Moonshots or Innovation.

Longevity Moonshots like Partial Reprogramming require new drug modalities, such as prophylactic gene or cell therapy, which have never been explored in humans. Longevity Innovations, meanwhile, are more incremental advancements, using preventative clinical trials with new drugs that have established modalities, like small molecules and proteins, both of which have been successfully used as single-disease preventatives before.

At Cambrian we have focused around 85% of the $160M we have raised so far on Innovative therapies, while still cultivating a few longer-term Moonshots on more complex technologies. The ultimate reason for this is straightforward - our mission is to get medicines approved for extending healthspan as quickly and reliably as possible.

Creating the first longevity drugs is going to be hard - that's why we need an effort at scale like Cambrian to have a good chance at it. Starting with Longevity Innovations allows for a simpler path to approval for these drugs for a very straightforward reason: innovative longevity drugs share many features with drugs that are already approved, safe, and have been on the market for decades. Small molecule drugs like statins, metformin, and SGLT2 inhibitors are well-understood treatments and preventatives in cardiac and metabolic diseases. If approving a new drug for longevity needs to change only one variable from what existed before (e.g., "We prevent heart disease, metabolic disease, neurodegeneration, and cancer instead of just one of those"), it can use the blueprint of previous trials as a pathway for approval. This makes it simpler for the company building those drugs, simpler for regulators like the FDA that review clinical trial data based on precedent, and simpler for doctors that will have to prescribe these medicines to their patients.

Once the first one or two generations of Longevity Innovations are approved, a new precedent will be set: a template for performing clinical trials preventing multiple diseases of aging simultaneously. With this precedent established, a technology that was once a Moonshot becomes an Innovation - "We are going to do a healthspan trial but with a gene therapy instead of a small molecule." ^[5]

Ultimately, these therapies will need to be tested in at least Phase 1 and 2 trials in the treatment setting, then Phase 2 and 3 trials in the prevention setting to reach approval. If these trials can't be done in 8-10 years, the investment case for these medicines falls apart because a company would have fewer than ten years left on its key patents to recoup its risk and investment. A more established clinical path for prevention will give all parties the confidence to move forward with faster, more efficient trials, contributing to a stronger investment case.

It's wonderful to see this explosion of interest in the longevity biotech world. I'm so heartened to see our community growing so rapidly, where scientists, entrepreneurs, and investors are uniting more and more around the idea that new technologies will help transform a sickcare system into a healthcare system over the next couple of decades. If we succeed, this will be the most fundamental shift in medicine since the invention of antibiotics. I'm grateful to have so many thoughtful and passionate people rowing in the same direction on this mission, whether they're pursuing Moonshots or Innovations - we will need both in the long term to deliver the largest positive impact on human health.

Notes:

1.    Ocampo, et al., Cell 2016, https://pubmed.ncbi.nlm.nih.gov/27984723/

2.    Lu, et al., Nature 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134/

3.    Browder, et al., Nature Aging 2022, https://www.nature.com/articles/s43587-022-00183-2

4.    Importantly, these claims aren't being trumpeted by the scientists working in these companies, who I think are overall taking a disciplined approach to evaluating their science

5.    Also worthy of noting, the idea of prophylactic gene therapies, such as would be used in the context of a partial reprogramming moonshot, is itself being derisked by companies like Verve and Precision, both of whom are pursuing gene-editing approaches to eliminate the gene PCSK9 from the liver as a way of reducing cholesterol levels and reduce risk of heart disease. If this work is successful, it will further derisk the second half of the partial reprogramming Moonshot around prophylactic gene therapies.