The Life Extension Advocacy Foundation (LEAF) volunteers were at the recent Undoing Aging conference in Berlin, and spent much of their time interviewing a selection of the attending scientists and entrepreneurs. The interviews are being published at the LEAF blog as they are made ready, and here I'll point out the latest. The research and development communities focused on treating aging are becoming very diverse. A wide range of activities are underway, driven by an equally wide range of views on the nature of aging and where best to intervene. Most work at the present time, well represented in these interviews, involves upregulation of stress responses, attempts to encourage greater stem cell activity, reduction in chronic inflammation, greater mitochondrial function, and other forms of overriding the regulation of aged metabolism, forcing it into a modestly better state.
As regular readers well know, I am strongly in favor of an alternative strategy, meaning a focus on the damage that causes aging. Striking as close to the root of aging as possible is the best path forward. That damage must either be repaired or made irrelevant, whichever of those two options turns out to be easier and faster in each specific case. If damage is removed, then the operation of metabolism will largely take care of itself. This should also be less challenging than any other approach: there are comparatively few root causes of aging and comparatively many downstream issues. Further, the causes are largely less complex than the forms of dysfunction and disease that result. Nonetheless, most present medical development initiatives attempt to compensate for the downstream issues of aging, and are thus both expensive and largely ineffective in the grand scheme of things. We need to do better than this if we are to live to see meaningful extension of healthy human life spans.
Can you tell us what kind of things Ichor Therapeutics is going to be doing?
One of the challenges in the aging space is that the kind of underlying discovery work that usually drives translational pipelines is really lacking, because the space is just so new. If you're looking at molecular targets of cardiovascular disease, cancer, or things like that, a lot of these targets have been thoroughly vetted by academic institutions in the peer-reviewed literature, and you have some level of confidence that the thing that you're going after is actually an appropriate target. But, because the aging space is so new, there's lots of new targets that are being discovered, but there hasn't really been enough time for academia to properly vet those targets. Some of them are very good real targets that we should be going after, and others are artifacts and might not actually be real or as impactful as we think.
So, at Ichor, we started doing, a while ago, a lot of contract work to try to help other companies that need to bring industrial-grade rigor to basic science and to early discovery and then move from that early-stage discovery work into full-on development programs, which are more akin to a traditional pharmaceutical pipeline. That contract work has grown; we've helped a lot of companies and worked with a lot of clients, and we've run into a need to have dedicated teams for project management and really making sure that all of the client projects get plugged into the pipeline to get our best efforts and everything else, and that's where Huda's coming in and spinning out all of our contract research into Icaria Life Sciences.
Our founding science demonstrated that there are certain proteins present in plasma that can confer effects on biological function in aging. Their relation to the processes of aging is supported by the observation that many of these functional proteins increase or decrease with age - we have termed these functional plasma proteins chronokines. There are beneficial chronokines known to decline with age that we can increase and thus delay the onset of aging-related disorders, and there are detrimental chronokines which increase with age that we can inhibit for this purpose. We have therefore focused on deeply understanding the plasma proteome as a source of therapies, both plasma-based and traditional pharmaceutical modalities like small molecule inhibition.
Our lead program is determining if TORC1 inhibition improves the function of the aging immune system and thereby decreases the incidence of respiratory tract infections (RTIs) in elderly humans. In a Phase 2a clinical trial, we found that RTB101, a catalytic site mTOR inhibitor (not a rapalog), led to a greater reduction in infection rates than the rapalog everolimus. We used very low doses of both RTB101 and everolimus in this trial, and both drugs were safe and well tolerated at these low doses.
When do you anticipate finishing clinical trials and being able to offer commercially available therapies for RTIs and other diseases that resTORbio is targeting?
We anticipate finishing two Phase 3 clinical trials, which will determine if RTB101 decreases the incidence of respiratory illness in people age 65 and older, in 2020. If the Phase 3 trials are successful, we anticipate submitting a New Drug Application.
What do you think is the best method of measuring telomeres?
We call the most sensitive assay TeSLA, for telomere shortest length assay. Most scientists use a qPCR assay that is not very reliable but easy to use. It is well established that it is the shortest telomeres that leads to replicative senescence. There are thousands of published papers using the qPCR making extraordinary claims based on very small differences in average telomere length. Other methods include TRF and Q-FISH, and these are intermediate in their ability to see some but not all the shortest telomeres.
What are your thoughts on restoring telomere length using transient telomerase induction as a therapeutic approach to aging?
It is a reasonable idea, and we are currently doing such experiments. Initially, it will be done ex vivo, e.g. in the cell culture lab, to prove it works and does no harm. We can then give individuals back their own cells, potentially with slightly elongated telomeres.