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Medicine
Thursday, July 12, 2018
/ neofile, stockadobecom
Boston – Everolimus, used in high doses as an immunosuppressant and cancer treatment, was reported at low dose in a randomized controlled trial in ] Science Translational Medicine (2018; 10: eaaq1564) in combination with another "rapalog" protected the elderly from infection.
The everolimus active ingredient, used as Certican for the prevention of rejection after organ transplantation and as Afinitor for the treatment of cancer is currently being discussed as an anti-aging drug. The mechanism of action is as follows: Everolimus, like the other rapamycin badogues (rapalogs), sirolimus and temsirolimus, is one of the mTOR inhibitors (mechanistic target of rapamycin )
The mTOR enzyme plays an important role in promoting aging processes. discussed. Inhibitors of mTOR have been shown to prolong the life of all species in experimental studies. Experts attribute this to a delay in immunosenescence. Immunosenescence describes the decreasing ability of the immune system to fight against pathogens. Because infections are among the most common causes of death in the elderly, agents that slow down the immunosenescence may prolong life.
The rapalogs are considered candidates because they primarily inhibit TORC1, one of the two mTOR complexes. ResTORbio, a member of the Novartis group based in Boston, is exclusively involved in the discovery of TORC1 inhibitors
After a long period of study in the animal, the results of a first study in the man are now available. In 12 centers in Australia and New Zealand, 264 subjects aged over 65, without medical conditions, were randomized to 2 groups of 4. They were given with 0.1 mg / everolimus or placebo, with 0.5 mg / everolimus or placebo, with 10 mg / BEZ235 or placebo, or with 0.1 mg / everolimus plus 10 mg / BEZ235 or
BEZ235, also called RTB101 by the manufacturer, belongs to rapalogues like Everolimus, but has a slightly different starting point. The combination of RTB101 and everolimus therefore seems useful.
First, the two TORC1 inhibitors appear to be well tolerated at low doses (important prerequisite for any anti-aging). During the 6-week treatment period, no security risk has occurred, according to Joan Mannick, cofounder of Boston ResTORbio, and his colleagues. The most common side effect seems to be diarrhea. On the other hand, blood glucose and cholesterol decreased during treatment
. The main measure of effectiveness was the immune response to a seasonal flu shot. Here, only the combination of the expected increase in antibody titers against the three components of the influenza vaccine was greater than 20%. Of the two monotherapies to everolimus, this target was only reached for one component at a time.
The benefit was more pronounced in the number of infections, which were first requested by telephone each week then monthly. While there were 2.41 infections per person per year in the placebo group, there were 1.49 infections with the combination of both TORC1 inhibitors and 1.61 per person per year with BEZ235 alone. . This represents a significant decrease of 38% and 33%, respectively, compared to the placebo group.
There was even a decrease in respiratory infections of 36% (combining the two TORC1 inhibitors) and 42% (among the BEZ235 inhibitors). monotherapy). There was no significant benefit in total infections and respiratory infections with everolimus monotherapy.
The results of the phase 2a study motivated RESTORBIO to a phase 2b study. Currently, people over 85 years (or over 65 years of comorbidities) are treated with different doses of BEZ235 alone or in combination with everolimus. The end point is the incidence of respiratory infections. The first results should be published by the manufacturer in the third quarter of 2018. Subsequently, the Novartis parent company may decide to conduct phase 3 trials as a prerequisite for approval.
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