Matt recently attended the 52nd annual meeting of the American Aging Association (AGE) in Madison, Wisconsin and met with several people doing fascinating work in or adjacent to the geroscience field.

His last guest from the AGE meeting is David Scieszka, a longevity entrepreneur with a unique background that includes work as a PsyOps specialist for the US Army. David is currently working on Vertical Longevity Pharma, a senolytics company that he spun out from his postdoctoral work. He previously lead multi-omics efforts at the biotech startup Norvoc Biosciences. David holds a PhD in biomedical sciences from the University of New Mexico School of Medicine, which he did concurrently with an MBA at the UNM School of Management.

In this episode, Dave and Matt give us a peek into the drug development process (TL;DR: it isn't straightforward or cheap), from facing investor skepticism to considering endpoints, dosage, and potential side effects to collecting rigorous preclinical data that will satisfy requirements for U.S. Food and Drug Administration (FDA) approval. They also chat about further opportunities for the drug's use in companion animals, a demographic that would also enable a potentially faster path to FDA approval.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Cellular senescence and senolytics: the path to the clinic - PMC

What is cellular senescence and why is it one of the most heavily targeted hallmarks of aging in longevity biotech? When cells encounter stressors and accumulate cellular damage, they have a critical decision to make: resolve the damage, commit cellular suicide, or enter a cell fate called cellular senescence in which they stop dividing, become death resistant, and release alarm signals known as the senescence associated secretory profile, or SASP. The SASP recruits the immune system’s aid and initiates an inflammatory response. Cellular senescence is thought to be beneficial in certain contexts such as pregnancy, wound healing, and preventing tumorigenesis—as long as the senescent cells are cleared away when the damage is resolved. But as we age, damage occurs at an accelerated rate and our immune system loses its ability to clear away senescent cells, leading to senescent cell accumulation. As senescent cells accumulate, the SASP drives chronic inflammation, fibrosis, and the conversion of more cells into the senescent state, giving them the infamous title of “zombie cells”.

In preclinical trials, senescent cells are demonstrated to accumulate at the site of aged/diseased organs. The clearance of senescent cells with senolytics has been shown to mitigate the progression of certain age-related diseases and biological processes associated with aging (e.g. cardiac hypertrophy, neurodegenerative disease, and insulin resistance).There are several different strategies to address senescent cell burden including killing senescent cells (senolytics), targeting the SASP (senomorphics), and boosting the immune system's innate ability to clear senescent cells (immunomodulators). The latter methodology is the focus of Vertical Longevity Pharma’s (VLP) platform technology. There are over two dozen clinical trials studying the effects of senotherapeutics on diseases as diverse as osteoarthritis, COVID-19, Alzheimer’s, and kidney disease currently in progress. One major challenge in the field is finding reliable biomarkers that are specific to senescent cells to improve senescent cell targeting, diagnostics, and prognostics.

Stop the Clock: New Therapeutic Strategy Targets “Old” Cells to Prevent Aging

Matt and David talk about VLP’s unique approach to targeting senescent cells, namely a senolytic vaccine that trains the immune system to recognize and clear senescent cells. This article covers the Suda et al. (2021) paper published in Nature Aging that serves as the foundational research for VLP’s platform technology. This research group identified a cell surface protein called GPNMB/osteoactivin that is specific to senescent cells and developed a vaccination that educated the immune system to target and clear osteoactivin-expressing senescent cells in three different mouse models. They found that a single treatment with their senolytic vaccine extended the lifespan of mice prone to atherosclerosis in a mouse model of accelerated aging. Interestingly, they also found GPNMB to be highly expressed in endothelial cells of patients with atherosclerosis, a senescent cell-driven pathology. David mentions that atherosclerosis may be the target indication for their proof of concept clinical trial.  If effective, VLP’s senolytic vaccination holds promise to mitigate the progression of one of the leading causes of death in the US.

Clinical Trials and Clinical Research: A Comprehensive Review - PMC

Matt and David talk through the rigors of the drug development process and how VLP is preparing to run the necessary mouse safety/toxicology studies and scaling development of a GMP (good manufacturing practice) batch of their senolytic vaccination in preparation for an Investigational New Drug application, the first major interaction with the Food and Drug Administration before phase one safety and dosing trials. This paper reviews the stages of the drug development process, including Pre-IND preclinical toxicology and drug manufacturing, IND submission including clinical protocols, administrative preparation and regulatory compliance, phase one safety and dosing trials in healthy volunteers (n = 20-100), phase two safety and efficacy trials (n = few hundred), phase three efficacy trials (n = several hundreds to thousands), and post-approval which consists of ongoing monitoring after a drug is in the market. Phase two trials are typically the major bottleneck for a drug's success.

How much do clinical trials cost?

This study evaluated costs data collected from seven high-revenue biopharma companies on 726 clinical trials from 2010 to 2016. The median cost of conducting a study from protocol approval to final clinical trial report was 3.4 million for phase one studies, 8.6 million for phase two, and 21.4 million for phase three trials. The largest influence on variability in cost was the number of subjects, sites, and visits required in the clinical trial. Add this to David’s estimation on the podcast of $5 million to prepare for IND submission, bringing the total to $38.4 million. A significant fundraising campaign for a new startup in the longevity space, but a small price to pay for the potential gains of healthy longevity and prevention of multimorbidity.

How does a cancer vaccine work?

Senolytic vaccines are not a completely novel idea— they are inspired by the development and growing success of cancer vaccinations. This review goes over the different strategies for developing cancer vaccines, as well as the challenges and promises of each. Each methodology involves identifying antigens unique to a given tumor and exposing them to a patient’s immune cells to help them recognize and clear the specific antigen-expressing cancer cells from the body. One potential challenge to overcome is the cancer cells' adaptive evasion tactics, which involve downregulating expression of the antigen or producing immunosuppressive molecules. Attempts to target senescent cells may not face the same challenges of cancer cell evasion, as senescent cells do not undergo cell division and have less adaptive, mutagenic capacity. That being said, targeting senescent cells has its own unique challenge: the immense heterogeneity of senescent cells within the body. Further, the biological aging process compromises the immune system’s ability to respond to vaccinations. Cancer vaccinations have demonstrated success in small pilot studies for pancreatic cancer, melanoma, and lymphoma, but the development of cancer vaccinations personalized towards a given patient’s tumor is extremely expensive. The advent and increasing popularity of machine learning platforms and big data is a major catalyst for the evolution of personalized vaccinations designed to target pathological cell types. Companies like VLP developing senolytic vaccinations can learn from the logistical hurdles, successes, and failures of cancer vaccinations.