The world of rejuvenation biotechnology is a rapidly changing and ever developing place. As with any disruptive technology, the challenges are significant and include not only the technical aspects of developing these technologies but also the hurdles of societal acceptance of the desirability of longer, healthier lives.
While I do not accept the idea proposed by some people in our community that there is any large and organized opposition to longevity technology, there are certainly some concerns about the idea. Sometimes, these are based on logical fallacies and cognitive dissonance, and we have addressed many common concerns here on the site.
However, I do not think such objections are the bulk of the challenge in bringing about societal acceptance. I believe it is more the case that the majority of people simply do not know about this fascinating field of science nor its potential.
There is also the case to be made that the majority of people probably do not even contemplate that they themselves will one day need the longevity technology our field hopes to develop. The old saying “You don’t know what you lost till it’s gone” is apt here, until people experience the limitations of their lifestyle and independence due to age-related diseases, it’s hard for them to visualize it happening to them.
That is not to say that reaching out to the public and engaging them about our field is a lost cause; it absolutely isn’t. Instead, it is really an opportunity for us to consider the messaging being used by our community and see where things might be improved or changed to better relate to what the person on the street will appreciate.
For me personally, I think the gateway to greater support for bringing aging under medical control, thus increasing human health and longevity, lies not in the radical but in the more incremental and visually obvious things. This means supporting technologies that may not give us radically longer lives but that may have an immediate impact that people can see and get behind. So, while an approach that reserves grey hair is probably not going to add many years to our lives, it could be the catalyst for greater support.
Also, success with these gateway technologies could also mean greater investor confidence and an increase in funding for more ambitious projects and technologies to be developed, and those could lead to significant increases in healthy human longevity and the end of age-related diseases.
Today, I am going to highlight some of these gateway technologies and the companies developing them along with some more ambitious ones that I think are worth keeping an eye on in 2021.
Led by Kristen Fortney, BioAge is a company that uses machine learning to analyze patient datasets in order to identify existing drugs and compounds that could potentially be used to treat age-related diseases. Late last year, the company closed a $90 million series C funding round and has two candidate drugs poised to enter clinical trials in 2021: BGE-117 and BGE-175.
BGE-117 is an inhibitor of hypoxia-inducible-factor prolyl-hydroxylase (HIF-PH). According to BioAge, the Hypoxia-inducible factor (HIF) pathway is associated with both lifespan and healthspan, the period of life you experience free from disease. Blocking or reducing the activity of HIF-PH allows the activation of the target HIF-1 genes, which are associated with tissue regeneration, erythropoiesis, glycolysis, glucose uptake, vascular remodeling and angiogenesis. Through their activation, the potential to treat multiple age-related diseases may be possible.
The company’s second candidate, BGE-175, is an inhibitor of the PGD2 DP1 prostaglandin receptor, which plays an important role in the age-related decline of the immune system known as immunosenescence. According to BioAge’s proprietary aging data, BGE-175 influences various pathways associated with lifespan and healthspan. Reducing or blocking PGD2 DP1 receptor signaling influences several immune system mechanisms, activating dendritic and natural killer cells and reducing neutrophil infiltration. BioAge’s preclinical studies show that BGE-175 inhibits neutrophil migration and that PGD2 DP1 inhibition improves dendritic cell function, both of which counteract immunosenescence.
Perhaps the most immediate gateway aspect of this second candidate is its potential ability to combat respiratory infections, which includes COVID-19 and similar viruses. If successful in trials, BGE-175 could help to keep the immune systems of older people working better, allowing them to better resist infections and diseases. In a pandemic situation such as COVID-19, such a therapy could find broad usage to boost disease resistance.
With a $21 million boost in January 2021 and FDA approval for a Phase 2A trial of its cell therapy for patients with end-stage liver disease, LyGenesis is a regenerative medicine company to watch this year. This spun-off biotech company from the University of Pittsburgh is developing an approach for liver regeneration via the injection of allogeneic hepatocytes into patient lymph nodes.
The regeneration of the liver is just the start; its drug development pipeline also includes plans for regenerating pancreatic, nephric, and thymic tissues. Being able to regenerate any of these organs would be groundbreaking and have an immediate and very positive impact that would be almost certain to garner wide public attention and support for the field. The work that LyGenesis is doing is a wonderful example of a gateway technology that could usher in wide societal support.
In December 2020, Gensight announced that its Phase 3 clinical trial was a success, meaning that mitochondrial gene therapy is now a reality in humans. The trial showed that the vision of those suffering from LHON, a mitochondrial condition that leads to loss of vision, could be restored somewhat through this gene therapy.
An expanded clinical trial is expected to follow shortly, and should the results of this remain positive, it is likely that this gene therapy will be approved and enter healthcare usage. Gensight is a true rising star and among the top biotech companies that you should be paying close attention to this year.
Led by Dr. Michael West, AgeX is a company developing an off-the-shelf embryonic-derived cellular transplant therapy system. It has two candidates: VASC1, which consists of vascular endothelial progenitor cells for cardiac ischemia, and BAT1, which is comprised of brown adipocytes for the treatment of age-related metabolic disorders, including Type II diabetes.
AgeX is also developing an induced tissue regeneration (iTR) system using epigenetic reprogramming. Its drug candidate iTR1547 is poised to enter phase 1 clinical trials for the treatment of chronic heart failure. iTR1547 is designed to restore regenerative capacity in a range of aged tissues, so if the initial trials for chronic heart failure are a success, it would be no surprise to see the drug expanded to other age-related diseases.
The AgeX candidates have been in development for many years, so we are hopeful that 2021 may see at least one of the candidates move into clinical trials.
2020 was a year when you couldn’t go anywhere without seeing the name Insilico Medicine in relation to publishing a new aging clock or deep learning algorithm. Among the company’s many achievements last year, it showed off a deep learning algorithm that was able to quickly identify novel DDR1 Kinase inhibitors.
It also announced a historic partnership with Taisho Pharmaceutical Company in Japan for the discovery of senolytic drug candidates. We are confident that this will lead to the identification of many new senolytic compounds that could potentially improve on the first generation of known senolytic drugs.
Insilico Medicine is proving that AI and deep learning are going to change how we discover and develop medicines forever, and we are looking forward to seeing what this company does in the coming year. One thing is certain, Dr. Alex Zhavoronkov and his team show no signs of slowing down, and they continue to drive the field forward.
Founded by Osman Kibar back in 2008, Samumed is a $12 billion biotech company developing drugs that target the Wnt signalling pathway. This pathway plays a pivotal role in stem cell renewal and differentiation and thus tissue regeneration.
Back in May, 2019 Samumed launched its Phase 3 clinical program of its candidate drug lorecivivint (SM04690) for the treatment of knee osteoarthritis. We are eagerly awaiting the results of its ongoing Phase 3 clinical trial, which we anticipate will finish in the later part of this year.
Lorecivivint has shown promise in early clinical phases, in which data suggested that the drug spurred cartilage regeneration as well as reducing patient-reported pain in cases of knee osteoarthritis.
If Samumed succeeds, lorecivivint could find broad application for treating multiple age-related conditions through the Wnt pathway. Many people suffer from age-related joint pain, and the crippling consequences of conditions such as osteoarthritis, so a drug that regenerates tissue would be a powerful demonstration that targeting the aging processes is the way forward. If the clinical trial results are positive, the impact on public perception and support for our field could be significant.
2020 was a bad year for many of us, and it was no exception for senolytic development company Unity Biotechnology. Back in August 2020, we reported on the disappointing news that its Phase 2 study of senolytic drug candidate UBX0101 had failed.
The drug is an MDM2-p53 inhibitor designed to treat osteoarthritis of the knee, but it suffered a spectacular failure in this trial. There are a number of potential reasons why: it could be that the target tissue just did not contain enough senescent cells using that particular pro-survival pathway for their removal to achieve much, that senescent cell accumulation does not play a key role in osteoarthritis, that the drug simply did not remove senescent cells, or even that senescent cell clearance in humans is not beneficial as it is in other animals. The reason remains unclear.
It really serves as a reminder that our field is highly challenging and that setbacks and failures will happen. This is just how science is: it takes time, failures, blood, sweat, and tears before success. However, despite some people declaring Unity a lost cause, it is my view that they could still turn things around.
It has another candidate drug, UBX1325, a Bcl-xL inhibitor that targets a different pro-survival pathway that senescent cells use to evade destruction, and this drug could potentially be Unity’s salvation. UBX1325 is in Phase 1 trials to treat diabetic macular edema, and results are anticipated during the first half of 2021. Should the initial results be positive, then a Phase 2 trial is sure to follow, and things could start looking up for Unity again.
Unity was always in a hard place, being the first senolytic company to reach trials and leading the pack. Any failures would be particularly hard on this company, but there is a pack of other senolytic companies hot on its heels with second-generation drugs and therapies, such as plasmid-based approaches. Therefore, even if Unity’s second roll of the dice does not pan out, there are plenty of other potential successors ready to step up. That said, Unity may well rise like the legendary phoenix in 2021, so keep your eyes on it.
We have been keeping our eye on this joint venture between Juvenescence and Antoxerene, a portfolio company of Ichor Therapeutics, as it is developing senolytic drugs that target the FOXO4-p53 pro-survival pathway. FoxBio launched in 2018 with $10 million of equity financing and drug development experience from Juvenescence combined with Antoxerene’s library of small molecules.
Juvenescence recently announced its plans to go public within the next six months or so, at which point it will be possible to own some of FoxBio. It has been a while now since that initial launch, so hopefully this news indicates that we may hear some news on the senolytic front from the company in 2021.
Senolytic Therapeutics is a biotech company that is a part of the Boston-based Life Biosciences group of companies co-founded by Dr. David Sinclair. It has two senolytic candidates, STX519 and STX434, which, given the time they have been in development, could potentially be ready for clinical trials this year. Based on the presentations from this company that I have attended, it seems that its future trials will be focusing on fibrotic diseases of the liver, lungs and kidneys.
Another biotech company that we are keeping an eye on this year, Numeric is a spin-off of the Erasmus Medical Center in the Netherlands and is developing a treatment targeting FOXO4-p53 using the FOXO4-DRI peptide originally discovered by Dr. Peter de Keizer. It is planning a clinical trial of its candidate drug NBT-103, which will likely be for addressing neuro-inflammatory or autoimmune diseases, in the second quarter of 2021.
Oisin is probably taking the most unusual solution to senescent cells with its gene therapy approach, which involves a DNA construct. The DNA plasmid encodes a suicide gene, caspase-9, the activity of which is regulated by the promoter for p16, a gene that is commonly strongly expressed by senescent cells and is central to cell cycle regulation.
This genetic payload is encapsulated in a neutral-lipid nanoparticle, which allows it to be delivered to the target cells and unloaded directly into the cell cytoplasm. The DNA transgene remains inactive and only switches on in p16-expressing cells. As an additional safety measure, this does not destroy the cell; instead, a low dose of rapamycin is required to activate the senolytic treatment fully and cause the senescent cell to die. It also has a spinoff company called OncoSenX, which is using the same technique but is focused on the p53 promoter instead for treating cancer.
It has been a while since we heard news from the Oisin team, so I am hoping that 2021 might be the year that the company announces that it is finally ready to begin clinical trials.
Rubedo Life Sciences
Having closed an $11 million seed financing round, Rubedo Life Sciences plans to launch Phase 1 trials for pulmonary fibrosis this year. This company, founded by Dr. Marco Quarta, has been developing a senolytic treatment that takes advantage of the elevated levels of beta-galactosidase observed in senescent cells in order to destroy them.
The research of Drs. Irina and Michael Conboy over the last decade or so has increasingly supported the approach that periodically filtering aged blood of harmful factors could spur youthful tissue regeneration and stem cell function. Certainly, their many animal studies have continued to suggest that it could be possible to “reset” the signature of aged blood and restore it to a more youthful state thanks to the multiple feedback loops in our biology.
Filtering the blood of the various problematic factors that drive aging and block tissue regeneration could be achieved using an already approved technique known as apheresis. This is a medical procedure that involves removing whole blood from a patient and separating the blood into individual components so that one particular component can be removed. The remaining blood components then are reintroduced into the bloodstream of the patient.
Turning this into a treatment that could potentially de-age old blood would require some modification of the standard procedure followed by rigorous clinical trials to ensure that it is optimally safe and effective. To that end, the Conboys have founded the startup biotech company IMYu to bring next-generation apheresis to the clinic, and I anticipate that we may hear about a clinical trial this year.
Looking forward to a better year
I could have easily written twice as much as this and named many more exciting companies that are working in this space and worthy of attention, but I will leave it here for now. While we are by no means out of the woods yet and COVID-19 continues to make its presence known, I remain positive that 2021 will be a better year and that there is much to look forward to in the field.
January 15, 2021
I think this decade (2020-2030) will be the one where we will have a lot of human data and if they are conclusive and visually apparent (skin / hair …) they could greatly change the perception of aging and could arouse greater interest from the public and weaker hostility to rejuvenation therapy, as well as a possible change in political regulations.
I can’t wait to see what this year has in store for us.
January 15, 2021
I didn’t know that Oisin’s therapy required rapamycin.
January 15, 2021
Jim, according to the information I read below in Nature journal it uses a very low dose of rapamycin to promote the dimerization of caspase-9 which initiates the killer protein.
January 20, 2021
Thanks Steve for an excellent and super detailed answer to my nagging questions once again.
I saw the recent news that David Baker’s lab at UCSF have developed an artifical protein that can detect proteins/other molecules within a cell and in response reveal a bioactive peptide.
It seems like this could be combined with Oisin’s nanoparticles to more selectively target senescent cells or to target mutated proteins within cancer cells.
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