RTB101 and immune function in the elderly: Interpreting an unsuccessful clinical trial

The biopharmaceutical company resTORbio, Inc. Recently announced termination of a phase 3 clinical trial evaluating the ability of the drug RTB101 to improve immune function in the elderly. The company reported that the first stage of the PROTECTOR1 trial did not meet its primary endpoint for reducing clinically symptomatic respiratory illness in healthy older adults. Although RTB101 has been described as an inhibitor of the mechanistic target of rapamycin (mTOR), the PROTECTOR1 trial was not a test of the geroscience hypothesis. Unlike the geroprotective compound rapamycin, RTB101 has not been found to increase lifespan or delay age-related functional or molecular phenotypes in pre-clinical animal models. RTB101 was first developed as an inhibitor of phosphoinositide-3-kinase (PI3K) with secondary inhibitory effects on mTOR. It’s ATP-competitive mechanism of action is distinct from the allosteric inhibition by rapamycin and does not specifically target mTOR complex 1 over mTOR complex 2. Clinical development of rapamycin and other specific mTOR complex 1 inhibitors to target age-related indications continues to be robust, and there is growing momentum for translational geroscience, with numerous clinical trials planned or ongoing in this area.