Trial of mTORC1 Inhibition Improves Immune Function in Older Individuals
Inhibitors of mechanistic target of rapamycin (mTOR) are arguably the most reliable of the current crop of compounds that slow aging by targeting stress response mechanisms, improving cellular health and resilience to some degree. The observed gain in life span in mice and lower species is likely to be much larger than the outcome achieved in longer-lived species such as our own, as that is unfortunately just the way things work for this class of approach to aging. Short-lived species evolved to have far greater plasticity of longevity in response to environmental circumstances.
The health benefits in old humans that can be obtained using mTOR inhibitors may well still be broad and sizable in comparison to most currently available medical technology for the treatment of age-related disease, but this is as much a suggestion that present technologies are not all that good, as it is a reflection of the utility of mTOR inhibitors. It seems likely that they won't hold a candle to approaches that are based on repair of underlying damage, such as those of the SENS portfolio.
The core challenge in developing therapies based on inhibition of mTOR is that mTOR forms two complexes, mTORC1 and mTORC2. These complexes have quite different roles in our cellular biochemistry; the unwanted side-effects of rapamycin stem from its inhibition of both complexes. Ideally, inhibiting mTORC1 but not mTORC2 is the way to go, but it has taken some years for drug candidates capable of this feat to be identified and progress through a development program. Here, one of these programs reports success in a human trial that targeted immune function in older individuals - and if you like the sound of the results here, just imagine how much more could be achieved through actually repairing the causes of immune failure with aging.
resTORbio today announced newly published data from a Phase 2a clinical trial demonstrating that target of rapamycin complex 1 (TORC1) inhibitor treatment improved immune function and decreased incidence of all infections, including respiratory tract infections (RTIs), in people aged 65 years and older. RTIs in particular are a significant health risk for the elderly with life-threatening consequences and few treatment options.
"Inhibition of TORC1 has extended both lifespan and healthspan in multiple pre-clinical species. The results of this Phase 2a trial raise the possibility that TORC1 inhibition also has health benefits in older humans. In the Phase 2a trial, TORC1 inhibitor treatment was associated with a clinically meaningful reduction in the incidence of infections in people aged 65 years and older and an enhancement in the function of the aging immune system as assessed by influenza vaccination response and antiviral gene expression. The results need to be validated in additional clinical trials, but may have broad implications for the treatment of diseases of aging that we are actively investigating with our TORC1 inhibitor program."
The data for this publication were gathered in a randomized, double-blinded, placebo-controlled Phase 2a study of 264 elderly volunteers at least 65 years of age without unstable medical conditions. Subjects were treated for 6 weeks with study drug and after a 2-week drug-free interval, were given a seasonal influenza vaccine. The incidence of infections was assessed for one year after initiation of study drug treatment. In the RTB101 monotherapy and RTB101+everolimus combination treatment arms, statistically significant and clinically meaningful reductions in the annual rate of infections of 33% and 38%, respectively, compared to placebo, were observed.
In a way it is not only slowing but temporarily reduced some of the effects of aging. I am sure that if the vaccination was performed half a year after the treatment the results would be much less important.
My guess based on the trial progress is this will be available sometime in 2020 if all the trials pass (phases 2b and 3 to go..), they have help from Novartis that has probably sped up the trials quite a bit, and 100 million in funding