Victor Bjoerk, biologist and member of the LEAF team, shares a report about a recent aging research conference that he attended in Germany. Victor is one of our more well-traveled writers, and he has the fortune to attend many interesting shows, events, and conferences in Europe. Today Victor reports on the DGfA Aging Conference and also interviews James Peyer from Apollo Ventures, an early-stage life science investor and company builder focused on translational research for age-related diseases.
An annual aging research conference
I took part in the yearly DGfA conference at the Max Planck Institute for Aging Research in Cologne on December 1-2, 2017. The event was organized by the German association for aging research, an interdisciplinary non-profit organization based in Nürnberg. Established in 1990, it conducts research on aging, including research on developing therapeutic options to treat age-related diseases.
The venue, the Max Planck Institute for the Biology of Aging, is an inspirational setting where you can see all the researchers in their labs working behind glass windows. This, combined with the high ceiling height and sterile white interior, made the setting look a bit like something from a sci-fi movie.
This was a highly technical conference with about 70 people attending, mostly scientists, and there were 21 different speakers in total. Compared to previous conferences I have attended, such as the SENS conferences, this was a purely technical conference, and with the exception of the last lecture by James Peyer, it was directly focused on basic aging research rather than life extension activism or a business perspective.
While I cannot give specifics because much of its data is unpublished as of yet, the talks covered a wide range of topics, such as the genetics behind longevity, cellular senescence, and the biomarkers of aging.
Since I have a big personal interest in senolytic therapies and understanding cellular senescence, which is at the forefront of true rejuvenation biotechnologies, the talks by Thomas von Zglinicki, Shoma Ishikawa, and Andrea Ablasser interested me a great deal.
The topic of senescent cells and removing them to improve health and combat age-related diseases has been an area of hot discussion, both in the academic and public domains in the last year. With human clinical trials in the cards for senolytic therapies that remove harmful senescent cells from the body, things are really getting close to the point where the first true rejuvenation therapies could start to arrive in the next few years.
The last talk by James Peyer was particularly interesting; it was quite different from the others, as he talked about translational research. Translational research is a discipline in biomedical research that aims to expedite the discovery of new diagnostic tools and treatments by using a multi-disciplinary, highly collaborative, “bench-to-bedside” approach. James is the founder and Managing Partner of Apollo Ventures, an early-stage life science investor and company builder that focuses on breakthrough technologies for treating age-related diseases.
He talked about how to translate the research on animals into practical and effective therapies for humans and the challenges and solutions they face. This recent TED Talk with James gives a good idea of the kind of things he talked about during his lecture at the conference and should give you a good feel for the kind of work he is involved in.
I was lucky enough to have the opportunity to ask James a few questions about his work.
It currently takes a global average of 17 years to bring a new drug to market; what changes do you think could be made to the clinical trial and regulatory processes to improve them and reduce the time and effort it takes to get them tested and approved?
This 17-year number includes what I think of as three primary pieces of a “therapeutics generation value chain.” I think that none of these three pieces can or should be elided, but there are ways to improve upon all of them, so I will try to take them in turn. In short, however, the issue with that 17-year number is that it is, by necessity, based on data 17 years old. The 21st century has already brought and will continue to bring innovations that will reduce this number.
First, you have to create the idea for a drug, which often means understanding or validating some basic biology or designing an assay or animal model to test whether a therapeutic could work. This work is often done in academia and takes a substantial chunk of those 17 years. As an example, CAR-T cell therapies were first devised in the early 1990s, but it wasn’t until 2014 that the current generation of drug trials which have now been approved really got going. This stage is being sped up by our increasing understanding of the interconnectivity of biological systems. We are finding roles for new pathways in diseases and new ways to modulate these pathways faster than ever before, which will speed up this stage.
As an example, when I was doing my Ph.D., I did some research on stem cells that required making genetically engineered mouse models. It took a bit over two years to generate those mice. With CRISPR, the companies I’m working with can now do the same work I did in three or four months. Similar sorts of efficiency improvements are being seen with ESC-based models. This sort of technical improvement will reduce the time to the generation of good assays and the understanding of biology.
Second, you have the development and optimization stage. This is often, but not always, when a therapeutic idea gets moved from an academic lab to a start-up company, because the skills for doing this part of biology are quite different than the first part. Once you have some interesting biology to explore, you need to iteratively test dozens or hundreds of small variations on a single therapeutic modality to see which one will work best in people. Then, you need to test whether that drug is not just effective but also safe. The time that it takes to do this varies enormously, depending on the individual history of the therapeutic involved, but at Apollo, we usually look for compounds that can go through development and optimization between one and a half to five years.
I like to say that right now we are actually living in a renaissance of drug development because the tools to do optimization have become so much better. Recent advances in crystallography, NMR, and machine learning applied to chemistry have massively increased the speed and accuracy by which we can develop new, better drug candidates. This work is the “nitty-gritty” of drug development but is really super important.
Finally, you have the clinical stage once you’ve got a single therapeutic candidate that you’re ready to advance to trials. These can take a long time, but it’s very dependent on the disease. Back to the CAR-T example, Novartis received breakthrough designation for their CAR-T, which allowed it to get approval in only about three years for children with rare forms of blood cancer (Acute Lymphoblastic Leukemia). I am personally a big fan of clinical trials and think that overall the FDA has done a fantastic job over the past decade to balance the safety of patients with rapid approvals.
As we look towards indications where the unmet need is lower and the potential patient populations are healthier (e.g., diabetes, sarcopenia, multi-morbidity indications, early-stage dementia), clinical trials are necessarily long due to the fact that people need to be followed to know if the treatments are safe. I believe what is needed here is a handful of very good long trials which create a repository of biomarkers that can later be used as surrogate endpoints to shorten the time it takes to do these difficult trials (think cholesterol as a surrogate for reduced stroke risk). This will allow us to more easily use the tools of modern medicine to prevent disease.
As a last point, one of the things that I think won’t necessarily shorten the timelines to test drugs, but will make many more of them appear, will be to improve the success rate of drug trials. As our models for human diseases get better and better, the chance a drug will make it through clinical trials goes up. This number is very important because it impacts that very scary $2.4 billion “cost to develop a drug”, which accounts for all the failures of drugs along the way. As that number comes down, the number of companies that can be created and invested in goes way up. Right now biotech companies have about double the rate of approvals per clinical trial as traditional pharma company approaches, which is part of the reason I see early-stage biotech companies as a beacon of excellent investment in the next decade or two.
Do you think there are political regions where one can better succeed with translational research, which policies are important and why?
The US and Europe are where it’s at, for better or worse. Japan is doing interesting things with stem cells, and China is rapidly modernizing. Australia is being incredibly innovative with its trial models and may become a major player in the future, but developing drugs is expensive, and investors ultimately need to see a return on the financial risk that they’re taking on a biotech company. That means approvals in the US and Europe.
As we move towards trials for preventative medicine, the willingness of institutions to accept validated biomarkers as surrogate endpoints will probably drive where those trials go. We may see a world where drugs approved for one purpose (say, diabetes) are tested elsewhere for their preventative properties based on the willingness to look at surrogate endpoints. However, the future will have to tell.
The success rate for therapies to translate from mice to humans is often quite low; do you believe mice are still a valid model for developing new drugs and therapies, and, if so, why?
Absolutely yes. I’m a huge fan of mouse models, both because we’ve learned an enormous amount from them and the alternatives (fish, worms, non-human primates, human cell culture, human organoid cell culture) all have major disadvantages compared to mice, especially post-CRISPR where we can make better mouse models faster. Historically, the success rate for translation from anything to humans has been low, and mice are no exception here. I would say that one of the things driving this suspicion is the tendency to conflate a genetically homogenous mouse tumor with actual human cancer. For oncology, certain types of mouse models are incredibly poor proxies for human cancers; however, mouse models with spontaneous tumor generation that is genetically heterogeneous and using mouse xenotransplantation models as a way of studying primary human tumors have both been able to show very promising results.
I think the main lesson here is that we have to be incredibly careful and thoughtful with our decision to accept a mouse model as a true surrogate for human disease. We should constantly be challenging ourselves to ask “yes, it works in this model, but how close is this model to what’s actually going on in a human? How can we make a model that mirrors the human pathology better?” If we do this, mice will continue to be a wonderful tool for research.
You have talked about metformin as a potential drug for improving healthspan, but what do you think about translating more robust approaches, such as the repair-based ones that seek to tackle the aging processes themselves, a la SENS and Hallmarks of Aging?
I have been an advocate of repair-based approaches to aging since before SENS was called SENS. Apollo’s primary mission is to identify and aid the translation of therapies that repair and rejuvenate tissues and organ systems while simultaneously treating existing human diseases. Metformin, NMN, glucosamine, and other approaches derived from good aging science that are now ready for clinical testing are important to establish precedents for how we can use our understanding of the biology of aging to do clinical trials and get drugs approved for the prevention of disease.
I have done a bit of math this year, and it’s amazing to me that if one of these geroprotectors gives just one year of extra healthy life, it blows the value of the best cancer therapeutics out of the water in terms of a benefit analysis of the drug. Proving this to insurers, regulators, and investors is a major part of breaking the dam to ensure a healthy flow of investment and innovation into longevity and disease prevention.
What is your view about the market for pet longevity, and how do you think it will impact translational research and getting therapies for humans?
I think that the animal market can be a good proxy for human trials, as the barriers to doing long clinical trials are much lower since lifespans are lower in companion animals. I think that projects like Matt Kaeberlein’s Dog Aging Project could be incredibly beneficial in improving the health of companion animals and also in showing more concretely the benefits that humans may receive from such treatments. To my point about surrogate biomarkers, I think that as we do these companion animal trials, it is critical to find markers of response to each drug intervention that correlate with a reduced disease burden. These markers will have the greatest use as we pivot to human trials. My overall belief is that if we do things right, we will be able to move to human proof-of-concept trials for disease prevention before completing any more long-term animal trials – I think the scientific and medical justification for doing human trials for geroprotectors is already sufficiently strong.
The poster sessions
The poster sessions afterward were also interesting and covered a variety of topics, such as advancements in understanding cellular senescence and measuring different aging biomarkers. This provided an excellent opportunity for me to ask researchers questions and discover how their findings could be implemented to help out with life-extending therapies.
I also took the opportunity to promote the upcoming Undoing Aging Conference in Berlin that will take place on March 15-17, 2018. The Undoing Aging conference will be bringing together the best researchers of aging to talk about progress and the future. LEAF is happy to report that we will be at the event bringing you interviews, reports, and the latest rejuvenation biotech news.
I also took the chance to meet up with some friends who are members of Heales, a Brussels-based NGO that has been working on promoting healthy longevity research since 2008. From left to right is me; Sven Bulterijs, who is a student at Ghent University and a former SENS Research Foundation employee; Alexander Tietz of Aachen University; and Adam Summerfield, a Ph.D. student on aging in Jena. I am working together with Sven Bulterijs to organize the EHA2018 conference on aging in November next year in association with Heales.
I enjoyed the DGfA conference a great deal, and I hope you have found my report from the event interesting. I look forward to sharing more of my experiences with you in the near future and to bringing you more interviews with the researchers working in the field.