The first 'gene silencing' drug for Alzheimer's disease shows "promise" said the authors of a new study, published in Nature Medicine.
Experts hailed the results as "promising" for Alzheimer’s disease, but caution that it's early days of the phase 1 trial and there's still a way to go.
There are over 50 million people worldwide currently living with dementia, mostly due to Alzheimer’s disease (AD), and this number is expected to double every 20 years. Tau plays a key role in the disease pathophysiology, and evidence suggests that lowering tau may reduce this pathology.
Dr Susan Kohlhaas, executive director of research & partnerships at Alzheimer's Research UK, told Medscape News 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." However, currently there are no treatments targeting tau, the study authors stated.
For most patients with AD, treatment remains limited to multidisciplinary management of symptoms, including pharmacological therapies that have no disease-modifying impact, explained the authors. Therefore, they said, additional disease-modifying treatments to prevent or slow progression of this disease remained a significant unmet need.
Exciting Approach to Treatment
The researchers set out to inhibit the MAPT gene, which provides instructions for making tau, and reduce tau levels, directly targeting a key disease effector mechanism in patients with AD.
"It’s the first time a 'gene silencing' approach has been taken in dementia and Alzheimer’s disease," the authors trumpeted.
Prof Robert Howard , professor of old age psychiatry, University College London, enthused that "stopping progression of Alzheimer's disease by interfering with the expression of the gene that drives production of tau – a protein that may worsen neurodegeneration – would represent a novel and potentially exciting approach to treatment".
For the randomised, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial to evaluate the safety, pharmacokinetics, and target engagement of a tau-targeting antisense oligonucleotide, MAPTRx, the researchers used a drug called BIIB080 (/IONIS-MAPTRx). This is designed to reduce concentrations of MAPT messenger RNA and thereby 'silence' the gene coding for the tau protein.
"This prevents the gene from being translated into the protein in a doseable and reversible way," said the authors, and added that lowered production of that protein will also alter the course of disease.
The trial involved 46 patients - 34 randomised to MAPTRx and 12 to the placebo group – all with mild AD, mean age 66 years, and generally similar across trial groups. Participants received intrathecal bolus administrations of MAPTRx (10 mg, 30 mg, 60 mg) or placebo every 4 weeks, or two quarterly doses (115 mg) during the 13-week treatment period, followed by a 23-week post-treatment period.
The primary endpoint was safety, and the secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid. The prespecified key exploratory outcome was CSF total tau protein concentration.
No Serious Adverse Events
Overall, MAPTRx treatment was generally well tolerated, with all participants completing the treatment period and over 90% of participants completing the post-treatment period.
Adverse events (AEs) were reported in 94% of participants treated with MAPTRx and 75% of participants treated with placebo. All events were considered mild (88%) or moderate (12%) in severity, but a greater percentage of participants receiving MAPTRx experienced mild AEs compared with those receiving placebo (62% vs 42%). However, the incidence of moderate AEs was similar between treatment and placebo groups. The most reported AE in participants receiving MAPTRx was post-lumbar puncture headache, which was generally mild in severity.
"No serious adverse events were reported in MAPTRx-treated patients," reassured the authors.
Dr Liz Coulthard, associate professor in dementia neurology, University of Bristol, found the study "exciting" because it showed the amount of tau can be altered, and also because it was a very "high-tec"” method of treating patients with Alzheimer's.
"One major drawback to this treatment," she cautioned, "is that it needs to be given by injection into the lumbar spine."
MAPTRx administration resulted in dose- and time-dependent reduction in the concentration of CSF total tau and phosphorylated tau181, with approximately 50% mean reduction from baseline observed 24 weeks post-last dose, the authors recounted.
Dr Catherine Mummery, consultant neurologist, UCL Queen Square Institute of Neurology & the National Hospital for Neurology and Neurosurgery, and trial lead, said: "The results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow – or possibly even reverse – Alzheimer's disease, and other diseases caused by tau accumulation in the future."
Emerging From the 'Amyloid Clearance Rut'
The authors conceded some limitations of the study, which included its small size, and that all the study participants were White.
Determining whether the reduction in tau was efficacious, and MAPTRx treatment- related effects on exploratory biomarkers, would require further evaluation in larger, well-controlled trials, which should also include a diverse patient population to adequately evaluate both efficacy and safety, acknowledged the authors.
"We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations," recognised Dr Mummery.
Prof Tara Spires-Jones, professor of neurodegeneration and deputy director of the Centre for Discovery Brain Sciences, University of Edinburgh, and British Neuroscience Association president, remarked: "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."
'Promising' Results, But In-Depth Studies Needed
Dr Richard Oakley, associate director of research at Alzheimer's Society not connected with the study, was also excited by the results. He told Medscape UK News. "This reduction of tau in the cerebral spinal fluid could reflect a reduction in tau build-up in the brain but we'd need to see more in-depth studies to confirm this." He suggested it could also mean "good news" for other forms of dementia associated with tau build-up, such as certain types of frontotemporal dementia.
Dr Kohlhaas said that the trial had demonstrated the drug was "hitting the correct target". She emphasised that although the early findings were "promising", there was much more to be done.
Prof Howard sobered that the study was a "long way" from showing that the treatment has a positive effect on progression of the neurodegeneration and symptoms of Alzheimer's disease. However, he granted it did result in a “measurable reduction” of tau concentrations in spinal fluid.
"After several decades stuck in the amyloid clearance rut", he felt the study represented an "important first step" in demonstrating that the treatment was reasonably safe.
"With more work like this, research will pave the way towards a cure," said Dr Kohlhaas.
Funding for the study was provided by Ionis Pharmaceuticals and Biogen. CJM reports advisory board membership for Roche, Lilly, Biogen, and Ionis; research grants from Biogen; seminar chair for Biogen; chair of data safety monitoring board for AD trial led by Imperial College; supported by the NIHR Biomedical Research Centre dementia subtheme at UCLH. MJ reports advisory board membership for Biogen Sweden AB and BioArctic AB. SD reports salary support from the Fonds de recherche du Québec–Santé; consultancies from Biogen, Wave Life Sciences, AZTherapies and Janssen Pharmaceuticals; advisory board membership and/or speaker fees from Eisai, Biogen, Sunovion, Innodem Neurosciences, HealthTech Connex, and QurAlis; he is also the cofounder of AFX Medical Inc. EGBV reports consultancies from New Amsterdam Pharma, Treeway, ReMynd, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, and Brainstorm Therapeutics. PI of studies with AC immune, CogRX therapeutics, New Amsterdam Pharma, Janssen, UCB, Roche, GreenValley, Vivoryon, ImmunoBrain, Alector and Alzheon and sub-I from DIAN-TU, Alzheon, Eli Lilly, Cortexyme, Biogen en Fuij Film Toyama. LM, KMM, CY, DL, DAN, RC, CFB, CJ, and RML are employees of, and hold stock in, Ionis. DLG, EH, and ER are employees of, and hold stock in, Biogen. The remaining authors declare no competing interests.