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The Strategy of mTORC1 Inhibition Fails a Phase III Trial


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Posted 18 November 2019 - 07:18 PM


The worst possible outcome when developing a clinical therapy is not an early failure. It is a late failure, in the final and most expensive phase III clinical trial, in which the therapy interacts with a sizable patient population, and after a great deal of time and funding have been devoted to the program. This result is far more likely for therapies based on mechanisms that have smaller rather than larger effect sizes, and where that smaller effect size varies from individual to individual for reasons that are not well understood - something that describes all too much of the past few decades of efforts to treat age-related disease. Unfortunately this worst case phase III failure just happened to resTORbio's mTORC1 inhibitor RTB101, in tests of its ability to improve immune function and reduce the burden of infection in later life.

The inhibition of mTOR, and specifically only the mTORC1 protein complex in order to reduce side-effects resulting from inhibition of mTORC2, is one of a range of potential approaches demonstrated in animal models to modestly slow aging via upregulation of cellular stress response mechanisms. It affects some of the same processes as calorie restriction and exercise. Another way of looking at it is that it pushes metabolism into a state that makes it incrementally more resilient to the accumulated damage of aging. However, all such strategies examined to date perform far better in short-lived species than in long-lived species, a situation that may occur at root because calorie restriction evolved to increase the odds of survival through seasonal famine. A season is a long time for a mouse, a short time for a human, and so only the mouse evolves to demonstrate a sizable relative gain in healthspan and life span due to a restricted calorie intake.

Nonetheless, the clinical evidence to date suggested that mTORC1 inhibition would produce enough benefits in human patients to be worth it from the patient perspective: a low cost pill that produces incremental improvement in the experience of late life medical conditions. I don't think that this outcome is worth it from the point of view of the enormous funding required for development and regulatory approval, however, not when there are far better options on the table, such as senolytic therapies to clear senescent cells and the rest of the SENS rejuvenation research program. The resTORbio team may have made a poor choice of indication to apply their therapy to - though given the promising results to date, I don't think that could have been known in advance. It may be that incremental gains through mTORC1 inhibition can still be obtained for patients with other age-related conditions, but nonetheless, this present failure should dampen our expectations to some degree for any and all other approaches based on stress response upregulation.

Failure in a late stage trial doesn't go unnoticed, and nor should it. It sends ripples through the biotech industry, since there are always networks of companies working on conceptually similar approaches to the therapy that failed at the final hurdle. The best outcome of such events would be for investors and entrepreneurs and researchers to gravitate towards better approaches to the treatment of aging - those with larger and more reliable effect sizes, by virtue of actually repairing the underlying damage of aging. Senolytic therapies are a great example of the type. As two decades of relentless fixation on anti-amyloid immunotherapy in the Alzheimer's industry demonstrates, this can take some time, however. The worst outcome would be for investment in the whole longevity industry to be damaged by failures in its first large trials, because naive investors have little to no insight into the technical and scientific differences between poor strategies and good strategies. This puts greater pressure on the senolytic companies to succeed in their initial trials, as they are up next.

resTORbio Announces That the Phase 3 PROTECTOR 1 Trial of RTB101 in Clinically Symptomatic Respiratory Illness Did Not Meet the Primary Endpoint

resTORbio, Inc., a clinical-stage biopharmaceutical company developing innovative medicines that target the biology of aging to prevent or treat aging-related diseases, today announced that top line data from the PROTECTOR 1 Phase 3 study, evaluating the safety and efficacy of RTB101 in preventing clinically symptomatic respiratory illness (CSRI) in adults age 65 and older, did not meet its primary endpoint, and that it has stopped the development of RTB101 in this indication. RTB101 is an oral, selective, and potent TORC1 inhibitor.

"While we are disappointed in these results, there are extensive preclinical data supporting the potential therapeutic benefit of TORC1 inhibition in multiple aging-related diseases, including Parkinson's disease, for which we have an active Phase 1b/2a trial of RTB101 alone or in combination with sirolimus. Multiple pre-clinical models have demonstrated that inhibition of TORC1 decreases protein and lipid synthesis, increases lysosomal biogenesis and stimulates the clearance of misfolded protein aggregates, such as toxic synucleins, that cause neuronal toxicity in Parkinson's disease. We remain committed to exploring the potential benefits of TORC1 inhibition in patients, and we look forward to the data from our Parkinson's disease trial, which we expect in mid-2020."

The PROTECTOR 1 Phase 3 trial was a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety and efficacy of RTB101 10mg given once daily for 16 weeks during winter cold and flu season to subjects 65 years of age and older, excluding current smokers and individuals with chronic obstructive pulmonary disease. The primary endpoint of the trial was the reduction in the percentage of subjects with clinically symptomatic respiratory illness, defined as illness associated with a respiratory tract infection, or RTI, based on prespecified diagnostic criteria, with or without laboratory confirmation of a pathogen.

The PROTECTOR 1 trial included 1024 patients who were randomized 1:1 to receive RTB101 or placebo administered once daily for 16 weeks. In an analysis of the primary endpoint, the odds of experiencing a CSRI were 0.44 in the placebo cohort and 0.46 in the RTB101 cohort. The Company plans to conduct detailed analyses of the PROTECTOR 1 study, including additional data on safety and secondary and exploratory endpoints, which are not available at this time, with the goal of gaining insights that may explain the difference in RTB101 activity observed in PROTECTOR 1 as compared to prior Phase 2 studies.


View the full article at FightAging




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