Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

Abstract

Background 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. MethodsWe did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for an RTI within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers. In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratoryconfirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed. Patients, investigators, and sponsor were masked to treatment assignments. All patients who received at least part of one dose of study drug were included in the primary and safety analyses. The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903, and the phase 3 trial was registered with ANZCTR, ACTRN12619000628145. FindingsIn the phase 2b trial, we recruited 652 participants in total between May 16, 2017, and Jan 10, 2018, 179 participants to part 1 of the study (randomly assigned 1:1:1 to RTB101 5 mg once daily [61 participants], RTB101 10 mg once daily [58 participants], or matching placebo [60 participants]) and 473 patients to part 2 (randomly assigned 1:1:1:1 to RTB101 10 mg once daily [118 participants], RTB101 10 mg twice daily [120 participants], RTB101 10 mg in combination with everolimus 0•1 mg daily [115 participants] or matching placebo [120 participants]). In our first prespecified statistical analysis of the primary efficacy endpoint for part 2 of the phase 2b trial efficacy of RTB101 10 mg in combination with everolimus 0•1 mg once ...

Interconnections between Inflammageing and Immunosenescence during Ageing

“…The switch between effector (T eff ) and memory (T mem ) cells involves metabolic changes mediated in part by the kinase mTOR [342]. This is of significant interest given the finding of improved T and B cell responses to influenza vaccination and reduced incidence of respiratory tract infections in older adults treated with mTOR inhibitors [343][344][345]. While such drugs are immune-suppressive at high doses and used clinically to prevent the rejection of transplanted organs, at low doses, they are immune-protective [346].…”

“…mTOR inhibition improves later life health and increases lifespan in mice and other experimental animals [419,445]; notably mTOR inhibitors also suppress pro-inflammatory SASP factors [15,446,447]. In human clinical studies, inhibition of mTOR successfully improved B and T cell immune function, increased vaccine response, and decreased overall infections in older adults [343,344], with stimulation of innate antiviral genes together with downregulation of pro-inflammatory factors [345], while MAPK kinase inhibitors, that overcome senescence in progeroid Werner syndrome patient cells [448], also suppress inflammation in skin fibroblasts from normally aged donors [449]. The inhibition of PI3-kinase, an upstream activator of mTOR, corrected the aberrant migration seen in old neutrophils [197].…”

Punicalagin Regulates Signaling Pathways in Inflammation-Associated Chronic Diseases

“…The mTOR signaling pathway has also been the focus of aging research [ 111 ]. Accumulated evidence has indicated that mTOR signaling pathways play an important role in cellular aging [ 112 ]. Although there is no direct report on punicalagin, the ability of pomegranate extract to improve aging-related diseases by regulating the mTOR pathway has been extensively studied.…”

Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets

“…In addition to the potential clinical development of 2-DG, the safety and efficiency of the PI3K/mTOR inhibitor BEZ235 (also known as RTB101 or Dactolisib) was also assessed in several clinical trials. While two phase II cancer studies reported the poor tolerability of relatively high doses [ 163 , 164 ], others could show, in phase IIb and phase III trials and with the aim of finding therapies to improve immune functions in the elderly, that BEZ235 is well-tolerated at regular low doses [ 165 ]. Moreover, they indeed observed an increased IFN-mediated antiviral immune responses in the elderly [ 165 ].…”

“…While two phase II cancer studies reported the poor tolerability of relatively high doses [ 163 , 164 ], others could show, in phase IIb and phase III trials and with the aim of finding therapies to improve immune functions in the elderly, that BEZ235 is well-tolerated at regular low doses [ 165 ]. Moreover, they indeed observed an increased IFN-mediated antiviral immune responses in the elderly [ 165 ]. While the authors could not statistically verify a drug-induced decrease in frequency or severity of viral respiratory infection, they also did not mean to exclude it.…”