In drug development, a failed clinical trial does not always represent the end of the road for an investigational drug. In fact, there can be much to learn from studies that did not achieve their endpoints – the outcomes, measurements, or events that are being evaluated by a trial. By examining what did not work and inquiring why, scientists can gather data that may help give future studies a better chance at success.

In some cases, the data gathered in a clinical trial that has not met its endpoints can still reveal a potential path forward for further study of a treatment. Analyzing data in new ways that were not part of a trial’s original endpoints through post-hoc analysis may also reveal subgroups of participants that may have a better chance of responding to a treatment.

Reinvestigating Lithium

Lithium carbonate, a drug currently used to treat certain psychiatric disorders, is an example of a treatment that has gone through this process in ALS. Although the preclinical evidence for lithium’s efficacy in ALS was controversial, a number of trials investigated its potential as a treatment, including a phase three trial whose results were published in 2013. While none of these trials demonstrated efficacy, a group of researchers in the Netherlands led by Dr. Ruben van Eijk decided to revisit the data from these studies in 2018.

Their goal was to investigate if a subgroup of participants in these trials might have responded to the treatment in ways that were not immediately apparent in the original data analysis. To this end, they conducted a meta-analysis – a study which reanalyzes data from multiple previous studies, in this case from three failed lithium trials. These trials had enrolled people with all forms of ALS, including sporadic and familial. The researchers wondered if, by stratifying the participants into groups according to their genetics, they might be able to identify subgroups of responders.

The researchers were able to obtain genetic information about participants in these trials who had either provided biological samples or simultaneously enrolled in other genetic studies. Upon analysis they identified people with a particular genetic variation, or genotype, in a specific location of a gene known as UNC13A that may have benefited from lithium. People who carried this genotype, referred to as rs12608932 UNC13A C/C, seemed to have nearly a 25% increased chance of survival over a twelve-month period during the trials.

This genotype in UNC13A is found in about 16% of people living with ALS that have a European ancestry. However, unlike more commonly known ALS-related mutations in genes like SOD1, C9ORF72, and FUS, this variation in UNC13A is thought to be a risk factor for ALS rather than a cause. A person with this UNC13A C/C genotype may be more likely to have ALS at some point in their life than the general population, but it is not a direct cause of the disease as with familial ALS mutations. This genotype may also influence aspects of the disease such as age of onset, location of onset, severity of certain symptoms, and duration of survival.

From Meta-Analysis to Trial

The results of the lithium meta-analysis were intriguing, but the researchers knew that they must be approached with caution. The original trials did not make a distinction between those who carried this genotype or not when participants were randomized into the placebo or active treatment groups. This meant that the number of UNC13A C/C carriers in each group may not have been properly balanced to account for whether this survival benefit was a random coincidence. Additionally, the number of participants in this subgroup was too small to provide reliable statistical conclusions about the drug’s potential efficacy.

However, the results were intriguing enough that the researchers decided another study for lithium carbonate in ALS in this specific genetic subgroup should move forward. They designed a new phase three trial that is currently recruiting in several European countries. The study aims to screen up to 1,200 people in order to ultimately recruit the ~16%, or 171 participants, who carry the UNC13A C/C genotype.

What we Can Learn from this Trial

There are many lessons to be learned from lithium carbonate’s second chance in ALS. It is an example of a drug that may still have potential in a subgroup revealing itself in the data of a nominally “failed” study. It demonstrates the importance of collecting data about the disease and working to better stratify the ALS population into subgroups. If the researchers behind the lithium meta-analysis were not able to access genetic data from these trials, they would not have been able to identify the group of people who were potentially benefiting from a drug that appeared to have failed.

At the ALS Therapy Development Institute (ALS TDI) we are working to make sure that comprehensive data from people living with the disease are available to researchers to help make discoveries like this more common. Through the ALS Research Collaborative (ARC), the longest-running natural history study in ALS, we work with people with ALS all over the world to collect data about their disease. These de-identified data are then made available to researchers through the ARC Data Commons. This online platform gives researchers access to nearly a decade’s worth of data, as well as powerful tools to analyze them.

While potentially important discoveries can be made by analyzing the data of a failed trial, it should also be acknowledged that these studies would not be possible without the incredible contributions and sacrifices of trial participants. These people living with ALS agree to take experimental treatments, which can carry significant risks. They also do this with the knowledge that they may be assigned to the placebo group. If a trial fails, many participants may not be able to participate in another one due to exclusion criteria or progression of their disease.

Therefore, it is critically important that any drug that reaches clinical trials has been vetted by quality preclinical research – strong and thorough evidence that it is likely safe and has the potential for efficacy in humans. That is why ALS TDI, the world’s most comprehensive drug discovery lab dedicated solely to ALS, is committed to identifying promising candidates for human clinical trials – and to making sure they have the best chance to succeed.

To learn more about ALS TDI and our research to end ALS, click here.

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