Details on the Failed Phase 3 Trial of the resTORbio mTORC1 Inhibitor

The short version of the story regarding the failure of resTORbio's phase 3 trial of an mTORC1 inhibitor targeting immune function and influenza infection in old people is that the FDA forced a last minute change of the phase 3 endpoint from the phase 2 endpoint of a reduction in clinically confirmed infections to a more nebulous outcome of whether or not people reported feeling better. Which is far from the worst offense that FDA staff have committed in the course of hindering the adoption of new medical technologies, but it is illustrative of the obstacle that regulators pose. We can all speculate as to what was going on under the hood here, and which influences led to this outcome.

To my eyes, the field of mTOR based therapies remains something of a sideshow when it comes to human aging and longevity. The same is true of many of the metabolic manipulation approaches based on upregulation of stress response mechanisms. These mechanisms are known to produce sizable effects in short-lived species, but not in long-lived species such as our own. Thus here, mTORC1 inhibition does not produce a startling and large effect on infection rate and immune function, and nor should we expect it to, but it is cheap and it does produce some effect. mTORC1 inhibition replicates a thin slice of the beneficial calorie restriction response, and we know what calorie restriction can achieve in humans; this sort of approach isn't the path to very large gains.

We 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 a respiratory tract infection (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 laboratory-confirmed 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.

The purpose of our trials was to investigate whether targeting ageing biology with mTOR inhibitors could improve immune function and decrease the incidence of RTIs in older adults at doses that were well tolerated. The mTOR inhibitor RTB101 10 mg once daily for 16 weeks was well tolerated in adults aged at least 65 years, increased expression of IFN-stimulated antiviral genes in peripheral blood, and decreased the incidence of laboratory-confirmed RTIs (the phase 2b primary endpoint), but not the incidence of clinically symptomatic respiratory illness defined as respiratory symptoms consistent with an RTI irrespective of whether an infection was laboratory confirmed (the phase 3 primary endpoint).

Several possible explanations exist for the divergent results of the phase 2b and phase 3 trials, including the change in primary endpoint and changes in the way respiratory symptoms were collected between the two trials. In the phase 2b trial, respiratory illness symptoms were collected during twice weekly telephone calls with patients and the primary endpoint required predefined symptomatic criteria to be met as well as laboratory confirmation of an infection. In the phase 3 trial, respiratory illness symptoms were collected in eDiaries that patients filled out each evening and the primary endpoint was based on symptoms alone without requiring laboratory confirmation of an infection. Multiple investigators in the phase 3 trial anecdotally noted that patients reported in their nightly eDiary respiratory illness symptoms such as cough or headache that were part of the prespecified diagnostic criteria for a clinically symptomatic respiratory illness even when the patient and the investigator did not think that the patient had an RTI.

Despite the negative phase 3 results, important lessons were learned from this clinical development programme that is the largest to date targeting ageing biology in humans. First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults. Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses). Further refinement of clinical endpoints and more precise identification of responder patient populations will be important in future trials of therapies that intervene in ageing biology to improve immune function in older adults.



You know what else can make the patients feel better? Heroin, cocaine amphetamintes. All those were used before as "snake oil" and they did work and made the people feel better.

Posted by: Cuberat at June 16th, 2021 3:05 PM

Every time I read mTORC1 Inhibitor this paper comes to mind:

Regulation of mTORC2 Signaling

'7.1. Feedback Control between mTORC1 and mTORC2
Feedback control loops exist between mTORC1 and mTORC2 [105]. mTORC1 negatively regulates mTORC2 via S6K1. S6K1, downstream of mTORC1, leads to inhibitory phosphorylation of IRS1 and also downregulation of IRS1 protein level [106,107,108]. Downregulation of insulin-PI3K signaling then inactivates mTORC2. S6K1 can also phosphorylate RICTOR at Thr1135, but the functional consequence of this phosphorylation is controversial, and it does not seem to affect mTORC2 kinase activity [109,110,111,112]. S6K1 can phosphorylate mSIN1 at Thr86 and Thr389 to inhibit mTORC2 integrity, but this is controversial (discussed in Section 6.1, Figure 2A).
mTORC1 regulates mTORC2 in another negative feedback loop via growth factor bound-receptor protein 10 (Grb10) [113,114]. mTORC1 phosphorylates Grb10 at multiple sites and stabilizes the protein. Grb10 inhibits phosphorylation of InsR and IRS-1/2, destabilizes IRS-1, and mediates the inhibition of PI3K signaling and mTORC2 activity.'

Is it really possible to manipulate mTORC1 without ((un)wanted?) effects on mTORC2? Or without triggering over compensation of upstream pathways?

Posted by: Jones at June 16th, 2021 3:23 PM

FDA forces RTB101 to use patient symptom report not hard bio endpoint of lab-confirmed infection so trial fails. Then FDA approves aducanumab based on hard bio endpoint of Aβ clearance despite lack of improvement in patient symptoms. Seems inconsistent.

There's disgruntlement w/ both decisions, but even w/o arguing against either individually it's easy to argue the inconsistency of symptoms vs underlying bio is problematic. If Aduhelm is okay based on only underlying molecular bio evidence, resTORbio should have that chance too.

(As I Tweeted at: a few days ago.)

Posted by: Karl Pfleger at June 16th, 2021 5:57 PM

A common mechanism for longevity

Folates are essential vitamins important for the synthesis of amino acids and nucleotides-the building blocks of our proteins and DNA. "We tuned down the activity of specific enzymes of folate metabolism in the worms. Excitingly, the result was an increase in lifespan of up to 30 percent," says Annibal. "We also saw that in long-lived strains of mice, folate metabolism is similarly tuned down. Thus, the regulation of folate metabolism may underlie not only the various longevity signaling pathways in worms, but also in mammals."

"We are very excited by these findings because they reveal the regulation of folate metabolism as a common shared mechanism that affects several different pathways of longevity and is conserved in evolution," adds Adam Antebi, director at the Max Planck Institute for Biology of Ageing. "Thus, the precise manipulation of folate metabolism may provide a new possibility to broadly improve human health during aging." In future experiments, the group aims to find out the mechanism by which the folate metabolism affects longevity.

Posted by: Robert Read at June 17th, 2021 2:25 AM

Simulating fasting benefits?

Identifying RagA as a switch in the 'energy-saving mode' is the starting point of new research lines. So far, researchers have studied what happens when RagA is permanently activated: animals are never in a fasted state, and the long-term consequences are serious. But what would happen if RagA were permanently inhibited?

"We want to explore this path," Efeyan says. "With partial pharmacological inhibition of this metabolic pathway, we might get the metabolic benefits of fasting without the difficulties of limited food intake."

Posted by: Robert Read at June 17th, 2021 2:29 AM
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