Roundtable: Tackling clinical development challenges within ageing science
Joan Mannick, Chief Medical Officer, resTORbio, Inc
Steven Braithwaite, Chief Scientific Officer, Alkahest
Moderator: James Peyer, Founder & Managing Partner, Cambrian Bio
JAMES: Let’s start with a quick introduction to give readers some context about the type of work you’re each doing in this space.
STEVEN: Alkahest is built on the science from the lab of Tony Wyss-Coray at Stanford, who identified that there are circulating factors in plasma that can rejuvenate or restore function in the ageing brain. This is a systematic anti-ageing concept meaning that we can develop anti-ageing therapies based on the plasma proteome, using plasma fractions as therapeutics not just in the brain, but driving anti- ageing biology throughout the body. Within the plasma there are also critical hub proteins that can be therapeutic targets in their own right.
We’re building clinical programmes based on plasma factions in areas like Alzheimer’s disease, Parkinson’s disease and broader inflammatory ageing disorders. We’re also finding individual protein targets in indications such as age-related macular degeneration and neurodegenerative disorders for more traditional therapeutic routes.
JOAN: resTORbio is a spin-out out of a program that started at Novartis targeting the biology of ageing as a new way to prevent or treat ageing- related diseases. The first pathway we’re focusing on is the activity of a protein complex called TORC1. In every preclinical species studied to date, inhibition of TORC1 activity extended both lifespan and healthspan. The function of some (but not all) ageing organ systems is also improved in older animals given TORC1 inhibitors. At resTORbio we’re tackling this one organ system at a time to see what translates to humans and what doesn’t.
In our first program we investigated whether TORC1 inhibitors improved immune function in older people. In previous Phase 2 trials we showed that TORC1 inhibitors enhance influenza vaccine response and decrease T lymphocyte exhaustion in older people. TORC1 inhibitors were also associated with a decreased incidence of respiratory tract infections in two Phase 2 trials, but not in our recent Phase 3 trial. We have to do a deep dive in the data to figure out the difference between the results in the Phase 2 and Phase 3 trials.
In the meantime, we have another program targeting neurodegeneration. TORC1 inhibitors have shown clinical benefit in preclinical models of Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, all of which have protein aggregation as an underlying pathology. TORC1 inhibitors have been observed to induce autophagy, which is a process by which cells clear protein aggregates. Therefore, TORC1 inhibitors may have clinical benefit in neurodegenerative diseases by inducing autophagy and clearing toxic protein aggregates. So at resTORbio, we’re moving ahead just one organ system at a time, doing rigorous science to figure out where the findings from the preclinical species will translate and have benefit in humans.
JAMES: Excellent, thanks to you both. Now as we dive into some of the questions, please don’t be afraid to give some detail about how this emerging ageing biology space that we’re all a part of is unique from traditional biotech development, and what makes ageing biology a different beast to tackle.
Let’s talk about overall development pathways. What are the special considerations that you have to take into account when developing a therapy based on the biology of ageing compared to developing a traditional therapy?
JOAN: One of the really tricky parts about clinical development in this space is that ageing occurs over a very long period of time. You have to pick ageing-related clinical endpoints that can be assessed in a shorter period of time. Figuring out those endpoints is critical because we have to have smaller proof-of-concept trials where we can get a go/no-go decision in a short period of time without a huge clinical trial that will de-risk later stage development. It has to be thoughtfully considered when moving the preclinical science to the clinic.
I think the other problem is that ageing is a risk factor for almost every disease.
The expanse of potential indications is enormous. Pinning down which indication will have the highest probability of success requires a lot of thought.
STEVEN: I think that’s a major issue, that ageing per say is not an indication area. There is no regulatory path for anti-ageing therapies. Our long-term goal is that we will develop therapeutics that modulate the biology of ageing and will have impact across multiple disorders. But practically, we have to go through a more traditional indication space at the moment and as Joan said, pretty much every indication except some genetic disorders and perhaps asthma, are age-related disorders. Therefore picking the right indication to target is key.
It’s also very hard to translate preclinical findings from a two or three-year old mouse to a human with a lifespan of eighty plus years. How is the biology different? We have to build translational tools to actually understand how we improve going from preclinical to clinical studies.
JAMES: I couldn’t agree more with many of those challenges raised. Tell me about some of the ongoing trials that you’re watching in this space right now?
STEVEN: I think we’re all watching the individual mechanisms that have been connected to the biology of ageing. The trials that Unity have been doing around cell senescence are very interesting. We’re all going to learn a lot from the deeper analysis of those studies. Even if the primary endpoints don’t hit, we’re going to learn a lot from secondary end points and a lot from the secondary biology.
I’m personally very excited to learn more from resTORbio’s studies. Again, even if they haven’t hit the primary endpoint, there is going to be a wealth of data generated that will help us learn the right utility of modulating mTOR pathway.
We have our own studies at Alkahest that are reading out now, taking a more multi-modal approach with a plasma fraction.
We’ll be presenting our top line data in Alzheimer’s disease soon, but the deeper analysis of biomarkers is what will be key to progressing field-wide understanding.
Clearly, one of the key studies in the ageing field is Nir Barzilai’s TAME study testing metformin in ageing. Key here will be looking at novel endpoints, at developments of co-morbidities and how we shift the onset of multiple disorders, as a model for how to take a long-term anti-ageing therapy forwards.
The other studies that I’m interested in are the broader studies looking at exercise or diets, for example. We’re going to learn a lot from these longer, broader studies which are non- pharmacological, particularly looking at how endpoints are changing there.
JOAN: I think Steven is spot-on. We hope the information gleaned from our Phase 3 trial will move the field ahead because we’ll learn more about how to improve trial designs and identify appropriate patient populations. We have to continue moving this preclinical science into humans with more rigorous, placebo-controlled trials. We need to learn what’s going to translate and what isn’t, and in which populations. Even though it’s, of course, very disappointing to have a negative trial, there can be a lot of very important and valuable information to be gleaned that will help future studies succeed.
JAMES: Absolutely. That’s the nature of biotech R&D broadly, right? We all have to recognize that not every trial is going to be a breakthrough. It is a risky business. I really applaud your willingness to say “this one didn’t work out exactly as we had hoped it would, but now we’re going to figure out what we can learn and how to adjust.” There are lots of nuggets of really interesting truth in this biology.
JOAN: Exactly. It’s really interesting. It can be hard to take the hits when you’re breaking new ground and the data doesn’t come out the way you expected. But we will all learn a lot from analysing what happens as we move this science into humans.
STEVEN: One thing I’ve really enjoyed about being in the ageing field is that we are forming a very collaborative community. In some ways we need to be pre-competitive at this stage. That’s something that this field has taken to heart and it has been very open about the studies going on. We just have so much to learn from each other.
JAMES: We’ve talked about existing trials within the current biotech development framework. Looking forward, would you describe what the ideal clinical trial looks like for ageing-related therapeutics? What patient population do you want to be able to treat? What kind of biomarkers or endpoints are you looking for?
JOAN: In the future we may be able to personalise ageing-related therapeutics. For instance it would be useful to develop biomarkers of ageing-related biochemical pathways and then use therapeutics targeting specific biochemical pathways in the specific patients who have dysregulation of the pathways of underlying ageing-related diseases.
STEVEN: I think there will be a sequence of what we need to learn from trials. In the short term we have to go through trials which have relatively rapid and a very mechanism-based, target-based readout. We can’t be doing trials that are five years long. We then need to be able to pick up exploratory endpoints in these trials which will help us learn more about long term efficacy. These short-term trials are going to be very targeted. We have to modulate factors which actually are problems for patients. We need to have functional outcomes with a therapeutic utility, while learning more about long term effects.
Decades into the future we’ll be talking much more about preventative therapies - prophylactic products we can take years before onset of symptoms. We can’t develop in that way right now. But the more we can learn from today’s trials about how we’re modulating longer term biology, the longer-term outlook is that we’ll have prophylactic therapies too.
JAMES: Is there a model, perhaps one that has been used in the past, that might lay the groundwork for future clinical development applicable to the ageing space?
STEVEN: It’s similar to looking at a biomarker like cholesterol. We’re going to learn that some of these biomarkers of ageing eventually translate to something, and that we can modulate a signal in the short term for longer term efficacy.
JAMES: So in order to get there, we might need to produce an equivalent to the Framingham Heart Study that laid the groundwork for the FDA approving cholesterol modulation as both an end point and as primary prevention. That was an exceptionally long-term study. Do you think we need to take lessons from existing short-term trials and initiate a long-term trial similar to the Framingham Heart Study? Or is there another way?
JOAN: A different way of thinking about this can be drawing on a field like oncology, where ageing is a result of signal pathway biochemical or biologic perturbations. Different perturbations are going to play more or less of a role in how each individual ages. We can then identify the pathway perturbations in different populations and target them more specifically with a personalised medicine approach.
JAMES: So you could take something like autophagy - cellular recycling mechanisms where we know that the rate of autophagy in cells tends to be higher when we are younger and decrease as we age - and look for a biomarker for broad rates of autophagy or autophagy under a fasted state or something equivalent to that. Then using that biomarker, we can justify an intervention like an` mTOR inhibitor targeted specifically to increase rates of autophagy.
JOAN: Right. For instance in neurodegenerative diseases, different patient populations may benefit from interventions targeting different parts of the autophagy pathway.
STEVEN: You make a very good point that we see increased heterogeneity as patients get older. We certainly see this a lot in preclinical studies, specifically increased heterogeneity in animals when we work with older populations. In every setting this makes running clinical trials even harder. The more that we can do to narrow patient heterogeneity through personalisation, the better the probability of a successful trial to actually develop these drugs.
JAMES: Do you think that ageing biology is big and impactful enough to become its own branch of the biopharma ecosystem, or will it represent a family of mechanisms that sit within existing umbrellas?
STEVEN: Five years ago nobody was talking about modulating ageing as a therapeutic approach. The biopharmaceutical sector was so indication-only based it was heretical to talk about modulating ageing. That has changed, and now it is more widely accepted that modulating the biology of ageing has a fundamental influence across multiple disorders. The FDA and other agencies are keen to address how to build therapeutics for the growing ageing population. So, I think there’s been a very rapid maturation of the field and an acceptance that ageing should be thought about as a primacy. We have to navigate through the hurdles of how to develop these therapeutics. But I really believe that it is going to become a fundamental target in its own right.
JOAN: People have to realise that if ageing is the biggest risk factor for most diseases and it’s modifiable, that becomes a whole new area of medicine and drug development that we haven’t previously targeted. My prediction is that it will develop into its own area in both biotech and pharma. It won’t just be a little niche.
JAMES: That’s very exciting! The last piece that I want to address in this discussion relates to something that I think we’re all pretty sensitive about, which is what’s real versus what’s hype in the ageing biology space? How much of the value is preventing disease, like modulating ageing has the potential to do, versus treating existing indications like today’s short-term trials are aiming to do?
STEVEN: We need to prove that we’re actually making an impact and that cannot be by conducting long term trials at the moment. We need to be having near-term impacts and we need to be learning about the potential for the long term through biomarkers. But right now, the value drive has to be on short term efficacy readouts that are really impacting individual disorders.
JOAN: Often times it is easier to demonstrate that a therapeutic can treat rather than prevent a disease in a clinical trial. However, targeting the biology of ageing either to prevent or treat diseases is exciting scientifically, because it is a previously unexplored area of medicine.
This article is an extract from the Longevity Trends 2020 report.
The report captures Longevity Leaders' extensive research into this space, including the most important longevity trends of 2020 that businesses, policy makers, scientists and the general population need to be aware of.
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