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expert reaction to Phase 2a trial looking at enhancing immune function and reducing infection in the elderly

A new study, published in Science Translational Medicine, examines whether TORC1 inhibition enhances immune function and reduces infection in the elderly.

 

Dr John Tregoning, Senior Lecturer, Imperial College London, said:

“The paper reports a study of the effect of drugs that inhibit the TORC1 complex on the response to influenza vaccination and infection in the elderly (older than 65 years). TORC1 transmits signals from the protein mTOR within cells, leading to a wide range of effects. Studies in mice and other species have shown that blocking mTOR signalling can extend lifespans, though it is not fully understood how this occurs.

“The authors performed a clinical trial comparing treatment with two different drugs that target slightly different aspects of the TORC1 signalling pathway. The study then measured responses to influenza vaccination and saw that volunteers administered a combination of two drugs (RAD001 and BEZ235) had higher levels of antibodies against influenza after receiving the vaccine. The group that received the two drug combination had fewer infections in the following 9 months, though it was not recorded what the infections were.

“The paper investigates a relatively small number of patients, but is well performed and the results robust. But as the authors state, more work is required to understand how 6 weeks of drug treatment can protect against infection up to 9 months later.

“The press release accurately reflects what was said in the paper.

“The seasonal flu vaccine is the best way of protecting the elderly from infection at present, but vaccines can be less effective in the elderly, partly due to the aging of the immune system. Re-awakening the immune system prior to flu vaccination could be an effective way of improving its efficacy in the group most at risk severe influenza disease. This was a small study and larger studies are needed to confirm the findings. There are potential concerns about administering additional drugs to the elderly and alternative methods, such as the inclusion of adjuvants (substances which boost the vaccine response), which do not require additional drug treatments have been shown to increase vaccine effectiveness in the elderly; so a comparison against these existing approaches would be of interest.”

 

Dr Zania Stamataki, Senior Lecturer in Viral Immunology, University of Birmingham, said:

“Immune defences to viral infections in patients over 65 are compromised, largely due to an exhausted immune system that is difficult to activate.

“This is a blinded, placebo-controlled study that reports a reduction in the self-reported incidence of infection in a cohort of patients over 65 years of age, following TORC1 inhibition.

“Interestingly, patients over 65 that received TORC1 inhibition showed evidence of better response to vaccination against influenza.

“This is a very interesting small to medium-size study that puts forward TORC1 inhibition as a valid target for therapies to boost immune responses during influenza vaccination in the elderly.

“Taking into consideration the caveats of the measurements of the incidence of influenza in this encouraging report, a larger study of this kind could demonstrate if TORC1 inhibition offers protection in patients over 65.

“Ultimately, TORC1 inhibition could form part of a regime designed to boost immune responses to influenza infection in the elderly.”

 

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene and Tropical Medicine (LSHTM), said:

“This paper is a report of a trial with four active treatment groups compared with a placebo group. There are two types of active treatment (RAD and BEZ), one (RAD) tested at two doses, a low (0.1mg) and a higher (0.5mg) dose), and also the combination of the low dose RAD with BAZ. Those in the trial were healthy elderly people.

“There are two main outcomes- firstly whether the response to influenza vaccination (and three types of vaccine were studied) seems to have a better response with the treatment assessed by blood tests rather than clinical features. Secondly, whether over the course of a year the number of infections in total was reduced with treatment.

“The study seems generally well designed and analysed, though the analysis did not seem to make a specific attempt to see if the combination worked notably better from a statistical point of view than the single drugs on their own.

“There were 52 to 54 patients in each group. Six out of 212 on active treatment had adverse events that led to discontinuation of the drug, but none (out of 52) on the placebo had such adverse events, which is suggestive of a fairly high rate of stopping due to adverse events.

“The evidence that the drugs alone or in combination, improved the response to flu vaccination was good but not totally consistent (the low dose worked better than the high dose and as well as the combination for one of the types of flu vaccination).

“The number of infections over a year ranged from 2.4 in the placebo group to 1.5 in the combination group. The single drugs were intermediate with the low dose RAD being slightly better than the high dose.

“The results show some small effects but are definitely not a dramatic breakthrough. The numbers of patients are too small to show that adverse effects of a serious nature will not occur with the treatment. The most vulnerable patients in whom the treatment would be most valuable if it were to be shown to be effective have been deliberately excluded from this early trial, and whether benefits will occur in them without adverse effects is unknown.

“The evidence that the combination is a breakthrough compared with the single drugs is very limited and the presented analysis does not seem to have focused on this in a statistically rigorous way.

“Does the press release accurately reflect the science?

Largely, but there is some over-emphasis on the effects of the combination of the two treatments.

“Is this good quality research?  Are the conclusions backed up by solid data?

This is generally good quality research with a sophisticated analysis, but the conclusions seem to be overstated relative to the presented statistical evidence.

“Have the authors accounted for confounders? 

Confounders are essentially irrelevant in a randomised study.

“Are there important limitations to be aware of?

The groups studied are healthier than those for whom the drug is intended and the numbers are limited.

“What are the implications in the real world?  Is there any overspeculation? 

The real world implications are uncertain as yet- it certainly wouldn’t eliminate the need for flu vaccination but might help improve the response to it. The effects are not dramatic but might be useful if confirmed in larger more representative groups.

“As this is a Phase 2a, how far off is this from being available to the public, should it show promise?

It is difficult to say, it depends on what other trials have been done and how they are progressing. It will probably be at least two or three years before a product could be licensed if it were to be in the future.

“If it does work, what impact will it have on seasonal flu?

It will, if it is shown to work at least as well in this study, improve response to flu vaccination which would be useful, but it seems unlikely to have a major impact.”

 

Prof Ilaria Bellantuono, Professor of Musculoskeletal Ageing, University of Sheffield, said:

“This is a very important study. It shows for the first time that drugs, which are able to delay cellular ageing, have a positive effect in older people and not just in animal models in the laboratory. The administration of these drugs for few weeks prior to flu vaccination improves the response to the vaccine and reduces the rate of infections in the following 9 months. It is clinically relevant because flu vaccination is less effective in older people and respiratory tract infections are one of the leading causes of death. They are one of the main causes of NHS crisis in winter. Going forward it will be important to understand the exact mechanism leading to the improved response, particularly whether the intervention has led to rejuvenation of the immune cells and therefore has a long lasting effect.  In addition, a similar study should be performed in older people with multimorbidity or frailty, who would be the real beneficiary of such a treatment. The patients taking part to this trial were still healthy and more likely to respond positively to the vaccine and the treatment. ”

 

* ‘TORC1 inhibition enhances immune function and reduces infections in the elderly’ by Joan B. Mannick et al. will be published in Science Translational Medicine on Wednesday 11th July. 

 

Declared interests

Dr John Tregoning: “Member of the Human Infection Challenge Network for Vaccine Development (HIC-Vac), which is funded by the GCRF Networks in Vaccines Research and Development, which was co-funded by the MRC and BBSRC. I have funding from the BBSRC and MRC, I am member of the NCR3s studentship panel.”

Dr Zania Stamataki: “I currently collaborate with various pharmaceutical companies, none of which on related subjects to this paper. No conflict of interest.”

Prof Stephen Evans :”No conflicts of interest.”

Prof Ilaria Bellantuono: “I have funding from MRC Arthritis Research UK, Horizon 2020, Cancer Research UK, and BBSRC, and I am chair of the BBSRC Bioscience skills and career strategy panel, and NC3Rs studentship panel.”

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