April 24, 2023

expert reaction to Phase 1b study of MAPTRx in mild Alzheimer’s disease

Results of a phase 1b trial, looking at Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease, has been published in Nature Medicine.

Dr Susan Kohlhaas, Executive Director of Research & Partnerships at Alzheimer’s Research UK

“Previous research has shown that the build-up of a protein called tau in the brain is linked with neurodegeneration and diseases like Alzheimer’s. In this early-stage trial, researchers used a new type of approach to cause a drug to ‘switch-off’ a gene called the MAPT gene, which makes the tau protein. This reduced the levels of tau in people with mild Alzheimer’s disease suggesting that the drug was hitting the correct target. The drug also appeared to be safe at the doses given in this small-scale trial.

“These early findings are promising but there is much more to be done. The next steps for this, work are to repeat the study in a larger, more diverse population. The great news is, further work is already underway.  A phase 2 trial of this drug is currently aiming to enrol 700 people and seeing this work replicated in this next trial and larger studies will be vital if we’re to see this treatment approach reach the clinic..

“It’s an incredibly exciting time in dementia research with each new finding bringing us closer to new treatments. Research like this shows just how vital clinical trials are if we’re to make a real difference to the lives of people affected by dementia. With more work like this, research will pave the way towards a cure”

Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, said:

“This is a really exciting study. Tau and amyloid are two proteins that build up in the brain and are hallmarks of Alzheimer’s disease – other studies are looking at how we can remove these toxic proteins and this research shows that we may be able to reduce the overall amount of tau, ultimately aiming to prevent it becoming toxic.  

“This reduction of tau in the cerebral spinal fluid could reflect a reduction in tau buildup in the brain but we’d need to see more in-depth studies to confirm this. It could also mean good news for other forms of dementia associated with tau buildup, like certain types of frontotemporal dementia.  

“This was a small study so we look forward to seeing the results from the larger, more in-depth second phase of the trial, which should indicate if this drug might benefit people with Alzheimer’s disease.  

“In the meantime, we urgently need to ensure that everyone living with dementia receives an early and accurate diagnosis, so they can benefit from disease-modifying treatments such as these when they are available.” 

Dr Liz Coulthard, Associate Professor in Dementia Neurology, University of Bristol, said:

“This phase 1 study is exciting because it shows that we can alter the amount of tau – one of the proteins that causes Alzheimer’s disease.

“This reduction is achieved by blocking the messages from DNA that make the abnormal protein within each cell. It is a very high tech method of treating patients with Alzheimer’s. We know it might be useful because a similar drug is now used successfully to treat a rare neurological condition of childhood (spinal muscular atrophy).

“As this is a phase 1 study, all it tells us is that the drug is good enough to take to full trials, i.e. the drug blocks the production of harmful protein without causing obvious dangerous side effects.

“Bigger trials are needed to test whether this effect actually helps individual patients. These trials are underway.

“This treatment works on a different protein to lecanemab, the drug recently licensed in the US and under regulatory review here.

“One major drawback to this treatment is that it needs to be given by injection into the lumbar spine (i.e. by lumbar puncture).”

Prof Tara Spires-Jones, Professor of Neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, and BNA President, said:

“This paper by Dr Mummery and team shows early stage results of a new drug being tested to treat Alzheimer’s disease.  The drug lowers levels of tau, one of the toxic proteins that clumps in the brains of people with Alzheimer’s. This study is a well-conducted, early stage clinical trial to be sure the drug is safe to use.  Researchers found that the new treatment was safe in the 34 people who received it. There weren’t any serious side-effects of the drug. Excitingly, in this small study there was also very promising reduction of tau in the cerebrospinal fluid after treatment.  While there is a long way to go in larger trials to determine whether this drug will help people living with dementia, the data are very promising. This type of treatment targeting tau has the potential to slow or even hopefully stop Alzheimer’s disease progression, so I very much look forward to seeing results from the next stages of testing.”

‘Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial’ by Catherine Mummery et al. is published in Nature Medicine

DOI: https://doi.org/10.1038/s41591-023-02326-3

Declared interests

Prof Robert Howard: “No conflicts.”

Dr Liz Coulthard: “I have been paid by Eisai, biogen, Lilly, Novartis and UCB.”

Prof Tara Spires-Jones: “I have no conflicts with this study.”

For all other experts, no reply to our request for DOIs was received.