Life expectancy has jumped from 35 years (1800) to 82 today (+134%); can we expect to live 150 healthy years or more by the end of this century? This is a shared belief of major visionary entrepreneurs including Jeff Bezos (Amazon), Larry Page (Google), Peter Thiel, Jim Mellon or Jack Dorsey (Twitter). Coupled with massive research investments, those bio-novice leaders have played a catalyst role in blooming dedicated VC funds and companies. According to Bank of America, the anti-aging market is expected to soar from 110 B USD today to 610 B USD in 2025 (+454%) while very limited number of FDA approved drugs are expected in the next 10 years. Addressing a decupling health market while flirting with leading age science, the race for anti-aging medications can’t be ignored by Life Sciences VCs. Pushing the sciences wall and limits up to immortality sounds folkloric and utopian but in front of us, the mammalian bowhead whale lives up to 200 years and the cnidarian jellyfish never dies. As cancers turn out to be a chronic disease for a majority of patients and cardiovascular accidents better predicted and managed, old-age symptoms managements and cells fatigue/ apoptosis mechanisms are guiding the next medical frontiers. Instinctively we understand that if we want the heart beats beyond 2.5-3 billion times in a lifespan, we shall dramatically improve quality of life in order to lower the pulse and revolutionize cell/ gene repair & regulation pathways. A transversal management that empowered the quality-of-life management, age-related symptoms treatments and breakthrough therapies that delay or stop the onset of age-related diseases.
SENOLYTICS: PURGING THE BODY OF DYING CELLS
By selectively killing senescent cells, this emerging class of small molecules have been explored by more than 20 biotechs. Considered as the cornerstone in age-related-diseases, this mechanism is known to decrease tissue regeneration and secrete an impressive number of pro-inflammatory cytokines and growth factors leading to chronic inflammation in its microenvironment. Senolytics destroy senescent cells while senostatics agents stop pro-inflammatory secretions. Presented as a defense mechanism against cancer, the irreversible process that leads to senescence is activated through the well-known p53/p21 & p16/ Rb pathways. Multiple type of senescent cells co-exist and it is acknowledged that multiple senolytic strategies should be considered to be effective. Last August 2020, the disappointed 12 weeks results of the lead UBX0101 from Unity in Osteoarthritis have raised fundamental questions on senolytics and clinical development plan, including the use of WOMAC score which is a subjective scale to measure pain. The stocks immediately dropped from 12.43$ to 3$ (-75%) and is now quoted to 7$. UBX0101 targeted MDM2 which is known as one of the most important p53 inhibitor but do not selectively act on senescent cells. In order to avoid toxicity, Unity has developed a local administration which was not clearly validated in PC studies and only one intra-articular injection was performed and analyzed at 12 weeks vs. baseline. Experts suggested that the anti-inflammatory property was transient and that more than one injection would have been needed. The company may have counted on a high placebo response rate owing to the analgesic solution of the placebo arm (salted solution). Week 24 results will be checked but the program has been discontinued. Other ways to neutralize p53 have been investigated, particularly the one targeting the transcription factor FOX04 that sequester p53 within the nucleus. FOXBio (Juvenescence, Kizoo) has shown promising Preclinical outcomes in mice (hair loss and kidney dysfunction improvement) and the same target (FOX04) is also investigated by Eternans with similar results. Understanding the most relevant senescent cells to target and more specifically having the most relevant biomarkers to prioritize subtype of senescent cells is the core expertise and ambition of Cleara (Apollo, FJ Labs). Markers (subclass of prostaglandin) are better understood and validated to know whether or not a specific senolytic product is working. The same with cell surface senescent cell proteins that could be promising therapeutic targets such as uPAR (urokinase plasminogen activator). Understanding when and how natural NK cells lose their ability to neutralize senescent cells is also a strong focus. If one restores innate anti-senescence functions of Natural Killer cells, major benefit could be envisioned. Indeed, senescence biology is the cornerstone of multiple therapeutic fields. Today, evidence has been collected to show that senolytics and senostatics mechanisms are directly involved in the onset of Cancer, Cardiovascular Aging, Cognitive Functions, Sarcopenia, Cachexia, Type 2 Diabetes Mellitus, Liver and Kidney tissues homeostasis, Osteoarthritis and Erectile Dysfunction.
WHEN REGENERATIVE MEDICINE IS BOOMING
Repairing, replacing or reactivating growth of critical cells, tissues or organs is probably one of the most ambitious goal of Future Medicine. Generating or activating stem cells, better understanding the role and time of action of growth factors, cell plasticity or developing tissue engineering methods have pushed the frontier and possibility to dramatically increase lifespan. The expected market forecast and growth is also outstanding! From 2011 to 2016, CAGR was already at 34% according to Goldman Sachs. Looking to multiple sources, the constant annual growth rate is expected to range between 12% to 28% with sales forecasted to 27 B$ in 2026!. In 2020, regenerative companies have raised a spectacular 19 B$ from VCs the double when compared to 2019! Big Pharmas such as Novartis, Takeda or Astellas are already involved in developing platforms or products in this franchise. Most promising fields of development include wound healing, cartilage replacement, cardiovascular diseases, certain type of cancer, neuronal impairments. So far, more than a dozen of regenerative medicines have been FDA-approved. To summarize, the outcomes are for the moment important with potential safety concerns (black box for Infuse/ Regranex in Tibia fracture); yet the overall benefit in term of regeneration or healing is not strong enough in order to fully treat injuries or diseases. The Belgian preclinical stage biotech Agomab who raised 62 M€ in Series B in March 21 (REDMILE, ADVENT FRANCE, PONTIFAX, ANDERA…) have developed a monoclonal antibody platform with greater stability that is able to mimic activation effect of growth factors such as Hepatocyte Growth Factors. Agomab who is ready to enter the clinical development phase will be one of the rare players able to tackle the complexity of functional tissue recovering. The attention raised by this early-stage development biotech is one of the multiple examples showing the booming of Regenerative Medicine.
SPEEDING THE INVESTMENTS AND VISIBILITY
Today the dramatic awareness and expectation raised by the antiaging technologies has been translated to a fast increase of capital availability. The central role handled by anti-aging pathways in a broad scope of degenerative and debilitating diseases, the leadership played by successful entrepreneurs and the closing of fully dedicated funds have played a synergistic role in building a totally novel medical/investment and market space. With more than 15 companies in its portfolio the 165 M$ London fund _Juvenescence_ is one of the pioneers. Ditto with the Longevity Fund (CA, USA), Apollo VC (Berlin), The Methuselah foundation (VA, USA) all fully dedicated to fund and to develop reverse aging sciences. In the US only more than 70 VC funds have already invested in companies targeting antiaging mechanism of actions including Sofinnova Investments, Atlas, Polaris or Orbimed. While the medico-regulatory pathway is still blurry (approving a drug that claim to increase the lifespan of 10 years or more is indeed pure science fiction) there are multiple geriatric conditions that could be targeted and delay the onset of irreversible complications. By targeting sarcopenia, the loss of skeletal muscle and functions, Biophytis initially funded by Seventure Partners and now a public company (Euronext and Nasdaq) is well positioned to lead this marketspace. Sarcopenia is an independent predictor of mortality, particularly to surgical patients. Fighting Sarcopenia or other conditions predictive to mortality for the elderly population should be the high priority focus to move to the next milestone. Combined with social, economic, behavioral and psychological factors, the science of delaying the onset of age-related diseases is already shaping our life expectancy score. A reality that will come with fundamental philosophical, political, economic and to a certain extend religious questions.
Edouard Caram
edouard@vclife.org
SELECTION OF ANTIAGING COMPANIES THAT ARE OR WERE PRIVATELY FUNDED
