The Strategy of mTORC1 Inhibition Fails a Phase III Trial

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.


its a bastard when this happens, but unfortunatley its biology.

Posted by: scott at November 18th, 2019 4:16 PM

The problem is that things like mTor, the sirtuin genes and metformin are so synonymous with anti aging that when drugs against those targets tank it could have bad consequences for the entire industry.

btw. a good target in cancer like BRAF almost tanked because of bad drugs, the skeptics where crying BRAF is BS (fueled by short-sellers) , could happen with senolytics.

Posted by: Tom at November 18th, 2019 10:15 PM

This merely tells us to be careful about what we are calling an "age related disease". I would have never considered "symptomatic respiratory illness" to be an age related disease. I've had more than my share of "symptomatic respiratory illness" since I was about four years old.

Posted by: NY2LA at November 19th, 2019 12:41 AM

You got it NY2LA. I'll never understand the targets that are chosen for these potentially significant interventions. They are always borderline irrelevant and potentially misguided. This is a great example of it. One of the most important mechanisms of action for mTORC1 inhibition is immunosuppression. So they go ahead and try to study a disease with colds/flu. And on top of that, they carefully exclude subjects from the study that actually might have some age-related disease. I couldn't design a more flawed study if I tried! These are not stupid people so there must be some reason, other than the science, why they make these decisions.

Anyway, I agree that the major danger here is damage to the reputation of anti-aging science. Those with even a little knowledge of the subject would throw this study right in the garbage and ignore it.

One last thing I think we can all agree on at this point is this. Most people here are "damage" folks, and I lean toward a "programmed" aging theory. But everyone should know by now that this nutrient-sensing pathway and calorie restriction is going to be a huge fail. We should have known since we have been messing with metabolism for 100 years now and not even slowed down the rate of one disease with it. Yes, I am enamored of mTOR and Sinclair's Sirtuins and AMPK. I WANT them to work. But why can't we test these things quickly, so that when they inevitably fail, we can move on without having wasted 20 years and millions of lives. I'll give Sinclair credit though. He is one of the few human beings I've known that is willing to change his mind. I suspect he knows the big wins will be in epigenetics and he has pivoted in that direction to his credit.

Posted by: Corey at November 19th, 2019 7:01 AM

This is why it makes no sense to go after small anti-aging effects. If for some reason we fail, we should fail for aiming at the stars not aiming for New Jersey.

Posted by: david gobel at November 19th, 2019 8:26 AM

"... because naive investors have little to no insight into the technical and scientific differences between poor strategies and good strategies."

So you are saying that scientific teams OrbiMed, Fidelity, Rock Springs Capital, not to mention all the bio-pharma people at PureTech and Novartis were "naive"

You really have a very poor understanding of how this area works

Posted by: James Sweet at November 20th, 2019 5:08 AM

@david gobel, exactly!!!!!

Posted by: Ariel at November 21st, 2019 11:56 AM

@James Sweet, yeah, Reason is 100% right! We worked with many investors, because we establish our bioengineering company. 99% of them are very stupid naive people who even do not understand the cosmic difference between selling WEB site and searching for enzyme, even several hours of explaining by giving many examples cannot fix that issue!!!!!

Posted by: Ariel at November 21st, 2019 12:04 PM

@James Sweet, also, you name several companies, you know, investors wish to make money, researchers wish to make papers and NONE of them wish to make working therapy! They do not believe in their work, that is much worse!

Posted by: Ariel at November 21st, 2019 12:07 PM

Attempting to do too much with one molecule

Posted by: Bill Sardi at November 24th, 2019 3:47 AM
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