The history of longevity biotech

Nine years ago I got interested in longevity as a result of an existential search for meaning. The only way to have an impact back then was to join an academic laboratory and at the time that wasn't an option for me. So I took a different path: technology. But I did keep longevity as my life's purpose. My fiancée loves to remind me how I couldn't stop talking about it in our first date. Lame, I know.

So at the beginning of 2023 I finally left my job as CTO because I wanted to start working on what I truly think is important. I've been developing products and growing teams in startups for over a decade so my first instinct was to start a longevity biotech startup (or join one that is aligned with my principles). So I reached out to hundreds of experts (founders, investors, and scientists) to understand the differences with starting software (or hardware) startups.

To my surprise, and ironically, the playbook is quite old. But most people I talked to didn't even mention the history of the companies that tried to commercialise drugs in the longevity industry. Maybe because it's hard to distinguish between fraudulent science pushed by intellectual dishonesty, and good intentioned but unlucky and bad timed strategy. Be that as it may, it is fundamental to understand the history of the industry you're trying to push forward. So let me walk you through some of it.

The first longevity biotech startup

Few people know this but the first longevity biotech startup, Geron Corporation, was founded in 1990 (and incorporated in 1992) by Michael D. West, an American biogerontologist. They secured an initial venture capital seed round from Venrock and went public in 1996. This is not uncommon as biotech startups often raise money through initial public offerings (IPOs) to support their expensive and lengthy research, development, and clinical trials.

Geron's main focus was to develop drugs based on telomerase activation and inhibition. Telomerase repairs telomeres, which are segments at the end of chromosomes that shorten with each cell division. This progressive telomere shortening is a mechanistic pathway involved in the aging process. It induces genomic instability and eventually leads to either apoptosis or cell senescence (which are different types of cell death). So theoretically activating the enzyme in normal cells could extend cellular lifespan, which could be use to treat multiple age-related diseases.

But, after some initial and successful research, they began to recognise the tremendous technical difficulty involved in delivering telomerase to human tissues as well as the potential risks of such therapy. So the company began to consider human embryonic stem cell based therapy as a more practical and safer approach.

Geron's strategy was to target mechanistic pathways involved in the aging process and secure regulatory approval initially for the treatment of specific diseases and subsequently for the prevention of multiple age-related diseases or for increasing human healthspan. This was a straightforward answer to a regulatory constraint: there was no clear pathway to bring geroprotectors to market.

But this strategy proved to be easier said than done and some people including the director of molecular biology, William H. Andrews, left the company in 1997. Two years later, in 1999, he founded Sierra Sciences to continue the work on telomerase activation focused on aging.

Michael left shortly after and joined Advanced Cell Technology (ACT) in 1998 as President and Chief Scientific Officer. He reconfigured ACT’s research towards the emerging field of regenerative medicine. They initiated multiple programs involving the concept of therapeutic cloning, with the aim of developing cellular therapies through cloning technology. ACT had the turbulent life typical of young biotechnology startups venturing into promising therapeutics. The company was later renamed to Ocata Therapeutics and in 2016 was acquired by Japanese pharmaceutical company Astellas Pharma for US$379M.

In 1998 researchers sponsored by Geron announced the isolation and culture of human embryonic stem cells in the laboratory for the first time. This type of cells have the ability to differentiate into any cell type. So theoretically the discovery would allow scientists grow new heart cells to repair damage from heart attacks, new liver cells to treat hepatitis, and new red blood cells for cancer patients. Geron's shares suddenly exploded. But the discovery also started a media and regulatory battle full of the ethical implications.

Historically, it takes a long time for great science to become a great product. In fact, the stem cell discovery was at an earliest stage of development, with animal, let alone human, trials many years away. It wasn't until 2010 that Geron finally got the green light from the FDA and were able to start the world's first clinical trial using human embryonic stem cells to treat spinal cord injury. But just a year later in 2011, Geron decided to discontinue their stem cell programs including the ongoing trial with the hope to sell or license the stem cell program to another company that would continue it. Which they did. In 2013, they sold their stem cell assets, including intellectual property, cell lines, and related assets developed from their discontinued human embryonic stem cell programs, to BioTime, now known as Lineage Cell Therapeutics, which is still operational today and has several assets in their pipeline for the treatment of ocular disorders and other diseases.

After three decades of a long and rough ride, Geron continue their efforts to bring to market a drug that treats a disease through telomerase inhibition. They are currently running several disease focused clinical trials for their oncology drug imetelstat. And while they have not yet achieved the monumental milestone of commercialising a product, they pioneered important research on stem cells, telomerase, and telomeres.

Geron's story resonates throughout the history of the first generation of longevity biotech startups.

History doesn't repeat itself but it rhymes

In 1999 Cynthia Kenyon and Leonard Guarente founded Elixir Pharmaceuticals to develop drugs based on two key pathways that influence lifespan: the insulin/IGF-1 signalling pathway and sirtuins, a class of proteins thought to be involved in aging. In 2003 they merged with Centagenetix, another longevity biotech startup focused on developing genomic therapies based on longevity genes to slow down the aging process.

Cynthia and Leonard were renowned biogerontologists studying the biology of aging. But Elixir took a disease-centric approach, targeting specific age-related diseases rather than the aging process itself. Their product strategy didn't look very different than any other pharmaceutical company. Even if they did have research programs trying to understand pathways that slow down the aging process to identify interesting targets to treat metabolic diseases. This was a pragmatic approach to work within regulatory constraints, as there was still no clear pathway for FDA approval of broad anti-aging treatments.

Unfortunately, Elixir's story ended kind of abruptly. They managed to secure a total of $98.5M in funding from venture capital over 4 rounds and they showed positive results in clinical trials for their oral formulation of mitiglinide administered in combination with metformin for the treatment of type 2 diabetes. Leonard Guarente, left the company in 2006 due to disagreements with investors about the focus of the company. And after backing off from going public in 2008, they entered into an agreement with Novartis for an exclusive option to acquire their type 2 diabetes lead oral ghrelin antagonist drug. Novartis had many candidates in their pipeline for many diseases and eventually Elixir's drugs were abandoned on the shelf. In 2014 Cynthia joined Calico, Google's 1.5 billion venture to dramatically extend human lifespan.

And it rhymes again

You may think that the history of just a couple of companies is not a true reflection of an entire industry. But everywhere you look the story is quite similar:

In 1991 Bernard Malfroy founded Eukarion to develop drugs that neutralise free radicals and protect cells from oxidative stress. Initially they intended to target diseases like Alzheimer's and Parkinson's. But the company started commercialising some of their compounds as premium anti-aging cosmetic products. Eukarion was acquired in 2004 by Proteome Systems which licensed the assets to Minerva Healthcare in 2007. In 2008 Bernard Malfroy started MindSetRx, a virtual company which is a continuation of Eukarion.

In 1992 Doug Wallace founded MitoKor to discover and develop drugs for the treatment of major diseases and conditions associated with mitochondrial dysfunction which include Alzheimer's and Parkinson's diseases as well as type 2 diabetes. Mitokor managed to secure a total of $41M in funding from venture capital over 2 rounds and in 2004 was acquired by Micrologix. Micrologix changed their name to Migenix and was acquired by Biowest Therapeutics in 2010.

One of Leonard Guarente's alumni, David Sinclair, founded Sirtris Pharmaceuticals in 2004 to develop his research into activators of sirtuins. It went public in 2007 and was subsequently acquired for $720M by of GSK in 2008. But after failing to develop and commercialise sirtuin-activating compounds, Sirtris was shut down in 2013. David is a prominent aging researcher who has made important contributions to the field, though some argue that he has a tendency to overstate the near-term implications of early stage research. He deserves much of the credit for getting the field under the spotlight. But it hasn't always been the kind of attention the field needs.

Klotho Therapeutics was founded in 2009 to develop therapies based on the Klotho protein regulating lifespan, health, and cognitive function. Initially the company is trying to slow down the progression of kidney disease. In 2017 the company managed to secure a total of $10M in funding.

In 2011 Nathaniel David founded Unity Biotechnology to develop drugs called senolytics that target senescent cells. The company has several products in their pipeline for ophthalmology and neurology that have shown both some disappointing and some promising results in phase 2 clinical trials.

Oisin Biotechnologies was founded in 2014 to develop treatments for age-related disease based on the removal of senescent cells. The company has raised a total of $9.5M and is still in pre-clinical stage with their main therapeutic platform. Oisin primary focus is on two areas: senolytic therapies for age-related diseases and therapies for cancer.

Some people are overly optimistic to the point of taking unnecessarily dangerous risks. In 2015 Elizabeth Parrish founded BioViva to use gene therapies that target specific genes associated with aging. Initially the company's purpose was to prove if those therapies work. But Elizabeth started self-experimenting in jurisdictions that allow it. She claimed that she was the first person to use gene therapy to reverse aging, which wasn't absent of controversy. Currently the company provides services to anyone willing to self-experiment in jurisdictions that allow it.

Turn.bio was founded in 2016 by Vittorio Sebastiano and Jayakrishna Ambati to develop therapies based on epigenetic reprogramming and reverse cellular aging. The company has several products in their pipeline in pre-clinical phase.

In 2017 Michael D. West founded AgeX Therapeutics to essentially continue the work started at Geron: apply technology related to cellular immortality and regenerative biology to aging and age-related diseases. AgeX is a subsidiary of BioTime (now known as Lineage Cell Therapeutics) and has several products in their pipeline in pre-clinical phase.

The list is much much longer, but I'm going to stop here for the sake of story.

What we've learned so far

It's not easy to learn hard truths about an industry that you are passionate about. But it is what it is. Of course, startups fail for many reasons and the sample size may be too small to draw unbiased conclusions.

By no means am I'm trying to be dismissive of folks who've been working on longevity for much more time than myself. Anyone who has advanced the science of aging even the tiniest bit is my absolute hero. I'm not in a position to evaluate the science behind all the assets because most of the information is not public. I'm just trying to learn from the past, mostly from a product and business perspective. And I hope it helps to have it written down.

The different strategies that these and many other companies followed are common answers to the same constraint: there is no regulatory pathway to bring geroprotectors the market. So they either:

• Develop pre-clinical assets and platform that may have value for other pharmaceutical and biotech companies.
• Commit to the traditional biotech playbook and treat an age-related disease through a drug that targets a specific pathway or mechanism of aging, collect data to support claims for other indications and expand the label of the medicine over time. This should result in physicians prescribing the drug off-label and even in running clinical trials for broader indications.
• Commercialise unproven products (supplements) or experimental treatments (gene therapies) in jurisdictions where the regulatory environments may allow such procedures.

The intrinsic scientific difficulties in translating early stage research into an approved treatment often stood in the way of commercialisation, despite the best efforts of companies and researchers. Some assets got acquired and abandoned and others are still on their path to the clinic. In a perfect world, nobody would forget on the shelf an asset that has the potential to slow down aging. But many factors beyond just the science can influence whether an asset continues along the development pipeline. Even the most promising early research can sometimes fail to translate into an approved product, due to the inherent challenges in drug development:

• The company pivots to a different therapeutic area and the asset is no longer core to their strategy.
• Leadership changes at the company and new decision makers have different priorities, so they discontinue programs started under previous leaders.
• Patent life expires before the asset has progressed far enough to merit continued investment.
• Another company develops a similar or superior asset that displaces interest in theirs.
• The company runs out of funding to progress all assets and must make tough choices about which programs to shelve.
• Leadership simply loses conviction in the asset's potential for unclear reasons and turns attention elsewhere.

It may be possible to treat an age-related disease by targeting a mechanism of aging and I'm confident some companies will achieve that relatively soon. But it could be that the treatment will be optimised for treating the disease; not for slowing down aging. Running clinical trials to get any drug approved for an indication is by itself extremely difficult. And the best way to increase the chances of success is to optimise every detail. It may be dosage, formulation, biomarkers, protocol, duration or anything in between. Running clinical trials for extending healthy lifespan is entirely different.

From an investment and commercial perspective, given the scientific and historical risks, a drug that targets a specific pathway or mechanism of aging to treat a disease has no superior value than any other drug. Unless that drug can slow down aging. But in more than 30 years, despite apparently promising science and significant funding raised, no single longevity biotech startup has succeeded to bring a product to market. Product as in: drug that has been approved by a regulatory agency following thorough clinical trials. So maybe it's time to consider a different strategy: assume the regulatory risk, target aging itself and do it preventive instead of curative. Preventive drugs approved for several indications already exist. So bringing to market drugs that slow down the aging process and prevent all age-related diseases is just one step away.