A new study published in The Lancet shows the results of Phase 2a and Phase 3 clinical trials for the effectiveness of mTOR inhibition to bolster the aging immune system against respiratory illnesses.
Immunosenescence increases disease risk
As we grow older, our immune systems become increasingly dysfunctional and less able to defend us from the many pathogens that seek to invade our bodies. This gradual deterioration of the immune system is known as immunosenescence.
The adaptive immune system is affected more by immunosenescence than the innate immune system. It affects our ability to respond to pathogens and harms long-term immune memory, making it a huge problem for the health of the older population.
Respiratory tract infections (RTIs) are typically caused by viruses and are a major cause of illness and death in people aged 65 years and over. This has become particularly apparent during the COVID-19 pandemic, as the risk of contracting and dying from this disease strongly correlates with increasing age. Almost certainly, immunosenescence plays a key role in older people’s vulnerability to contracting RTIs.
The immune system involves the activation of many genes, particularly ones that encode cytokines known as interferons (IFNs), which trigger antiviral gene expression in cells when they detect a virus. A stunted type I interferon response, typically the first line of defense against viral invaders, could be a key reason that older people are more susceptible to infectious diseases.
In addition, the autoantibody system attenuates IFN response to prevent damage from inflammation caused by pathogens. In individuals with mutations to the genes involved in IFN regulation that reduce the IFN response more than normal, researchers found COVID-19 infections were more severe and the risk of death was higher. This suggests that a person’s genetics may determine the clinical course of COVID-19 infection as a recent study concludes [1].
mTOR is the target of human trials
During aging, the mechanistic target of rapamycin (mTOR) signaling pathway is typically overactivated, which is part of the aging process known as deregulated nutrient sensing.
mTOR is composed of the mTORC1 and mTORC2 protein complexes. It senses amino acids and is associated with nutrient abundance. It is a kinase, which means it adds phosphates to molecules. mTOR is a master regulator of anabolic metabolism, the process of building new proteins and tissues. At any given moment, the metabolism is either breaking down old parts (catabolism) or building new ones (anabolism).
Reduced activity of the mTOR pathway has been shown to increase the lifespan of mice, yeast, worms, and flies. However, reducing mTOR activity too much is potentially harmful and low expression can interfere with wound healing and insulin sensitivity.
A 2014 clinical trial that targeted the mTOR pathway showed that mTOR inhibitors were able to boost the immune response in people over 65 to an influenza vaccine [2]. A phase 2a clinical trial in 2018 using mTOR inhibitor RTB101 showed an increased IFN response and improved antiviral gene expression. This resulted in decreased RTIs in people aged 65 and over [3].
Two more human trials that target aging
Recently, Dr. Joan Mannick, who was involved in the previous two studies, followed up on these findings with Phase 2b and Phase 3 trials [4]. The trials were conducted at multiple sites, randomized, double-blinded, and placebo-controlled to maximize the quality of data. The trial participants were given RTB101 in winter during the influenza season for a 16-week period.
Phase 2b saw 652 participants enrolled who all had an increased risk of RTIs and were aged between 65 and 85. The participants had underlying conditions, such as asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), or congestive heart failure, were current smokers, or had an emergency room or hospitalisation due to an RTI within the last year.
Participants were administered RTB101, a combination of RTB101 and everolimus (a rapalog related to rapamycin and an mTOR inhibitor), or a placebo. A daily dosage of 10 mg of just RTB101 significantly reduced laboratory confirmations of RTIs, which supported the previous 2018 Phase 2a trial results.
It failed to have any effect on smokers or people with COPD. It appeared to be most beneficial to people aged 85 or older and people aged 65 or older who had asthma. Worth noting was that treatment with RTB101 also reduced the percentage of patients developing RTIs with severe symptoms.
The Phase 3 trial saw the enrollment of 1024 people aged 65 and over. Participants in this phase did not have COPD and were not current smokers. Again, a daily dosage of 10 milligrams of RTB101 was used for the study group, and this was a placebo-controlled trial.
Moving the goalposts
Prior to launching Phase 3, the FDA requested a change in the primary endpoint from laboratory confirmation of an RTI to the number of participants who had at least one symptom of an RTI. This meant that compared to the Phase 2b, the Phase 3 trial involved participants who had a lower risk for RTIs and a revised primary endpoint that was less easy to associate with changes to immune function and efficiency.
Without laboratory confirmation that patients had an actual RTI, this change to the primary endpoint likely muddied the waters and is perhaps the reason why the study authors reported no significant reduction in RTIs. Unfortunately, this meant that this trial failed to meet its primary endpoint.
On the positive side, in both Phase 2a and Phase 3, daily administration of RTB101 boosted the expression of the IFN-responsive antiviral genes in blood samples compared to placebo. The authors suggest that boosting the activity of IFN-responsive antiviral genes might be an effective approach against coronaviruses or influenza viruses and resulting RTIs.
Abstract
The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. Therefore, we aimed to investigate whether oral RTB101 upregulated IFN-induced antiviral responses and decreased the incidence of viral RTIs when given once daily for 16 weeks during winter cold and flu season.
Conclusion
Despite the Phase 3 trial failing to meet its revised primary endpoint, taken together, the studies suggest that it is possible to target an aging process directly via mTOR in order to reduce the risk of developing RTIs.
This really comes back to one of the foundational ideas of rejuvenation biotechnology: to treat the aging processes directly to prevent diseases rather than treating the symptoms as modern medicine does. This could also help to prevent other types of infections in the older population and pave the way for the wide acceptance of treating aging directly to delay, prevent, or even reverse age-related diseases.
Literature
[1] Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., Hoffmann, H. H., Zhang, Y., … & Casanova, J. L. (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science, 370(6515).
[2] Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., Glass, D. J., & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. Science translational medicine, 6(268), 268ra179.
[3] Mannick, J. B., Morris, M., Hockey, H. P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Shavlakadze, T., Zhou, W., Quinn, D., Glass, D. J., & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Science translational medicine, 10(449), eaaq1564.
[4] Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., … & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. The Lancet Healthy Longevity, 2(5), e250-e262.
