LyGenesis’ Michael Hufford talks Longevity research programmes and investment.

Kicking off a series of interviews with our Advisory Panel members, we chatted to Michael Hufford, PhD, the CEO of LyGenesis, an organic regeneration company enabling a patient’s own lymph nodes to be used as bioreactors to regrow functioning ectopic organs.

Longevity.Technology: Michael is an entrepreneur and drug developer with experience developing small molecules, biologics and in drug delivery technologies, we were excited to get his take on the Longevity landscape during Longevity 2020 so we started by asking him for the lowdown on his current projects.

Michael Hufford: After nearly 10 years of academic research at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh’s School of Medicine, and another two years of IND-enabling large animal preclinical work as LyGenesis, it is now time to reap what has been sown:

• We have just completed our fifth preclinical study, and third large animal preclinical study, demonstrating our ability to regenerate functioning livers using the lymph node as a bioreactor.
• Our Investigational New Drug (IND) application will be filed with the FDA this summer. Our Phase 2 clinical trial protocol has been finalized, is now under IRB review, and we are targeting our first patient in during the 4th quarter of 2020.
• Our clinical trial is for patients with end-stage liver disease who are otherwise ineligible for a liver transplant.

(We decided to bullet point as these milestones as they are all worth noting: #impressive)

“… we are now going to advance our platform of organ regeneration and create a pipeline of regenerative therapies that were the stuff of science fiction just a few years ago …”

The transition from a preclinical to clinical biotech is one of the largest value inflection points in the growth of any biotech company – it’s not unlike adolescence, but thankfully without the acne. The question now is – what’s next? … For LyGenesis, we are now going to advance our platform of organ regeneration and create a pipeline of regenerative therapies that were the stuff of science fiction just a few years ago.

In parallel with our liver regeneration preclinical work, we have also been pushing forward on our ability to regenerate a functioning ectopic thymus, with a wide range of potential clinical indications. We have been focused on both aging (i.e. transplanting old mice with the thymus of young mice to look at the beneficial impact on immunosenescence) and a compelling orphan indication – the need for an ectopic thymus among children undergoing cardiac surgery, which often requires a thymectomy for surgical access to the heart. We now better understand the deleterious impact of this thymectomy procedure long-term on immune functioning, and this autologous application of our cell therapy would not require immune suppression, an added benefit of this particular clinical indication.

After closing our B-round of financing later this fall, we will be pushing forward on our existing positive small animal proof of concept studies showing that we can regenerate functioning pancreatic tissue (with clear implications of Type 1 diabetes) and renal tissue (for end-stage renal disease). Having now established a clear pathway with the FDA’s Office of Tissues and Advanced Therapies at CBER for our technology, we will be working to IND-enable these additional programs.

“The only way to be good stewards of invested capital is to dispassionately kill programs that don’t have a chance of succeeding, and focus your energies on those that have the potential to become revenue-generating products.”

But our philosophy for all of our work remains the same – kill quickly. Drug development is one of the riskiest, capitally-intensive enterprises on the planet; capital is precious, and time is more precious still.

The only way to be good stewards of invested capital is to dispassionately kill programs that don’t have a chance of succeeding and focus your energies on those that have the potential to become revenue-generating products. For our liver program, we can’t get the technology NOT to work. Time and again, in small and large animals across multiple models of liver disease, the hepatocytes engraft, proliferate, vascularize within the lymph node to form life-saving functional ectopic livers.

Too often great academic ideas, even from prestigious labs, fail to understand just how onerous the FDA IND-enabling programs can be, how high the bar is set among large pharma to partner with those programs. That leaves programs all too often inching forward, always starved for cash, limping along hoping to cross the road in the midst of an Indy 500. When you can’t kill a program – that’s when you twist the throttle and hang on.

Key now is to raise enough capital to transform this promising regenerative medicine platform into clinical therapies.

Longevity.Technology: New investors are coming to the sector all the time – are they well-informed about Longevity, or are there gaps in the education?

Michael Hufford: I think there are two sets of concerns. Among new investors to the space, especially seed or angel investors, I see a lot of enthusiasm for participating in the field, a lot of optimism and desire to put their money to work on something that could bring benefit to [not only] a specific patient population or clinical indication, but to our species and future generations. It’s worth pointing out just how remarkable this is.

“… there is something sublime about the desire to … fight disease, ease suffering, extend healthspan, and perhaps one day even extend Longevity …”

Mary Lasker, the famous philanthropist and health advocate, said it best: “Money is frozen energy that unfreezes itself when you pay people to work.” Investors could put their money into shorting stocks, or any number of other industries with the potential for financial rewards.

But there is something sublime about the desire to use ‘frozen energy’ to fight disease, ease suffering, extend healthspan, and perhaps one day even extend Longevity… it’s akin to lighting a candle versus cursing the darkness. If you find yourself in the position of holding that candle to light your way forward, then you need to know how long it will last, make the most of your time, and make sure you get as far with it as possible before it burns out.

The second concern is among more traditional life science investors and venture capitalists. We need these folks on our side – they bring with them the capital and connections to enable later-stage development, partnerships, and commercial deals that return capital to investors and fuel the next generation of companies. If they see Longevity and regenerative medicine as fringe plays, then the entire field suffers.

Put another way, as the saying goes, many VCs live on a teeter-totter [seesaw] that tips between fear and greed. If they fear the Longevity space today, then we all benefit when that fear becomes greed and later-stage capital flows to assets; that is the equivalent of financial fission that gets created when good assets make their way to companies with the R&D, regulatory, sales, and marketing capability that enable worldwide commercialization.

Longevity.Technology: Most investors appear to prefer seed-to-early-stage investing; have you found this to be the case in your networks?

Michael Hufford: I think it depends on the magnitude of raise that you need to advance your program. The valley of death that is so well known for drug development – where early-stage academic discoveries are starved for the cash required to make them truly viable drug development candidates – is equally applicable to Longevity assets.

For early-stage investors, I always suggest they retain 50% of their investment capital for subsequent rounds because the capital needs are so steep in biopharma. Even in a success scenario and you have a nice step-up in valuation, the capital needs grow by orders of magnitudes as you advance, so protect your investors by making sure they can participate in subsequent rounds of financing.

For those investing in Longevity, much of the science is so early that key is to make certain you have a clear sense of what will bring value – not publications, nor even patents necessarily, but how will the capital be used to de-risk the program for subsequent development, and is your goal the same one that the FDA and potential partners will value?

“… our desire to retire organ transplant waiting lists to the dustbin of medical history along with iron lungs and mercury ointments is completely understandable.”

Longevity.Technology: Organ growth is a fascinating area of the Longevity sector – do you find investors open to this proposition?

Michael Hufford: Thankfully, yes. Just a generation ago, organ transplantation itself was novel. And despite the clinical success rates of transplantation across multiple organ types today, we still face many of the same obstacles as we did decades ago – one donated organ can treat only a single patient, and the resulting imbalance in the supply-demand calculus means that dozens of patients die each day awaiting transplants.

What’s more, transplantation involves major surgery, which is both expensive and high-risk, meaning many patients with common comorbidities will never qualify for a transplant. So, our desire to retire organ transplant waiting lists to the dustbin of medical history along with iron lungs and mercury ointments is completely understandable.

We’ve found that investors are interested in both aspects of our value proposition – using our technology one donated organ can potentially be used to treat dozens of patients, and our cell therapy involves engraftment via endoscopic ultrasound, a low-risk and cost-effective outpatient procedure.

The challenge is in realizing the clinical reality of transplantation – if a transplanted tissue or organ isn’t vascularized, then it doesn’t survive, much less thrive.

3D printed organs and promises of widespread xenotransplantation of animal organs post-CRISPR make for great news stories but really frightening FDA briefing book submissions. The FDA as a regulatory agency is – rightly and by statute – concerned about patient safety, first and foremost. The work required to enable technologies is daunting on a good day, and even accomplished academics routinely underestimate, often by years and tens of millions of dollars, the effort required to get FDA buy-in for first-in-human studies. Some sayings are timeless for good reason – caveat emptor.