MAGNET-lithium study discontinued after interim analysis

The MAGNET-lithium study is a Phase 3 randomized, double-blind, placebo-controlled study testing lithium carbonate in a genetic subgroup of ALS patients (with the UNC13A gene). As part of the trial design, an interim analysis was performed to see whether there was evidence that the drug was working. Unfortunately, the interim analysis showed no survival benefit – which was the primary outcome measure – of taking the drug when compared with placebo. Due to these disappointing results, the decision has been made to terminate the study. Therefore, all study participants have been asked to stop taking the study drug immediately. 

Leonard van den Berg (chairman of TRICALS and principal investigator of the study): “We would like to express our gratitude to all of the patients, their families, the funders, and the study teams who were involved in the study. We are grateful for the time, energy, and determination of all people involved in helping forward research towards finding a treatment for this terrible disease.”  

“While this result may be disappointing, without people who are willing to join the trial, we would not have been able to rule out this potential treatment,” emphasizes Ammar Al-Chalabi (member of TRICALS’ executive board and investigator from King’s College London). “Every participant contributes to advancing our knowledge on ALS, even when the findings don’t lead to a new therapy.” 

The MAGNET-Lithium trial brought together international expertise in ALS clinical trials from Europe and Australia. Matthew Kiernan (CEO and institute director from Neuroscience Research Australia (NeuRA) and investigator from the University of Sydney, Australia): “Collaboration is key to finding new treatments for ALS. Despite the results, this study is a testimony to international collaboration.”  

Michael van Es, associate professor and head of the neuromuscular department at University Medical Centre (UMC) Utrecht, and one of the initiators of the MAGNET-Lithium study:

We were hopeful that lithium carbonate would prove to be effective for a genetic subgroup of ALS patients (UNC13a homozygous) based on post-hoc analyses of previous trials. The finding that lithium is not helpful is therefore very disappointing.

Despite this negative result, there are important takeaways from this study. We have been able to prove that lithium is not beneficial in the UNC13a subgroup of ALS patients. This study was the first clinical trial with a genetic modifier of the ALS phenotype as a therapeutic target. This study demonstrated that performing trials in the UNC13a subgroup of ALS is highly challenging, but feasible. The study also provides new insights into recruitment strategies and the natural history of this subgroup. We remain hopeful that the novel insights gained for this study will help design and conduct future clinical trials targeting UNC13a, leading to more effective treatment for this devastating disease.

About the MAGNET-Lithium study

The MAGNET-lithium trial is a TRICALS sponsored trial and is a sub-study under the international platform trial MAGNET (Multi-arm, Adaptive, Group-sequential trial NETwork to evaluate drug efficacy in patients with ALS/MND). The study recruited its first participants in mid-2021 and included a total of 88 participants. The MAGNET-lithium study has been executed by TRICALS in collaboration with international research centres: King’s College London and the University of Sydney. Globally, 10 centres participated in the study: 4 centres were located in the EU, 2 in the UK, and 4 in Australia. 

Lithium carbonate has a long history as a treatment for mood disorders, and several studies have highlighted the protective effects of Lithium carbonate in the brain. The MAGNET-lithium study investigated the use of lithium carbonate in people living with ALS who have a change in the UNC13a gene. A change in the UNC13a gene is not a genetic cause of the disease but is known to be associated with the prognosis and symptoms of MND. Analysis from previous clinical trials showed that participants with changes in the UNC13a gene would potentially respond better to lithium carbonate than those who do not carry the gene change. 

Collaboration

For the MAGNET trial, TRICALS collaborated with nine ALS associations in seven different countries: The Motor Neurone Disease Association, Alan Davidson Foundation and the My Name’5 Doddie Foundation (the United Kingdom), FightMND (Australia), Dutch ALS Foundation (the Netherlands), FWO with support of ALS Liga (Belgium), Ulla-Carin Lindquist stiftelse för ALS-forskning now known as ALS-fonden (Sweden), Thierry Latran Foundation (France), and Fundación Luzón (Spain).