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Levacetylleucine: a step forward in ataxia-telangiectasia treatment

Written by Juan Mato
Edited by Jacen Emerson

A new drug may help steady movement and improve daily life for people with ataxia-telangiectasia.

Small improvements in motor control can have massive effects for individuals living with ataxia-telangiectasia, a rare inherited neurodegenerative disease with no current FDA- approved treatment. Ataxia-telangiectasia, affecting 1 in 40,000 – 100,000 people, causes progressive, debilitating, and ultimately fatal damage to the cerebellum. This part of the brain is responsible for coordinating precise movements that allow us to complete basic daily tasks like dressing ourselves, cooking, and walking around. The loss of that motor coordination, as the name of the disease suggests, is referred to as ataxia, and significantly reduces daily functioning and quality-of-life in affected individuals.

The current study was performed in ten research hospitals across Europe, the UK, and the USA. A new drug called levacetylleucine was tested for its ability to safely improve patients’ ataxia symptoms and quality of life. In this study, researchers uncovered that 12-weeks of levacetylleucine treatment alleviated ataxia symptoms and improved quality of life in ataxia-telangiectasia patients, relative to placebo, with little adverse side effects. These promising results position levacetylleucine as a potential treatment option for individuals living with ataxia-telangiectasia worldwide.

An energy boost for struggling neurons

Given the lack of treatment options for individuals with ataxia-telangiectasia, it is crucial that researchers test new potential therapies that may improve patients’ lives. The underlying problem in this disease is a mutation in the ATM gene, which is important for repairing damage to DNA. When this mutation occurs, individuals develop issues in their brain cells, also called neurons. The mutation disrupts the production of ATP, the neurons’ energy source, making neurons dysfunctional and leading to ataxia symptoms. In addition, the mutation predisposes patients to develop cancer and weakens the immune system, making them more vulnerable to acquired illnesses. Levacetylleucine has recently emerged as a promising therapy in clinical trials for other fatal genetic neurodegenerative diseases such as Niemann-Pick disease type C. This drug can be taken orally and is able to enter neurons in the brain, where it can correct energetic imbalances caused by ataxia -telangiectasia’s damage to energy-producing pathways. As a result, neurons can produce more ATP, improving their function and protecting against the neurodegeneration that induces ataxia.

How it’s getting done

In this clinical trial, researchers tested the safety and efficacy of levacetylleucine on alleviating symptoms in 73 individuals with ataxia-telangiectasia. Researchers assessed participants’ baseline symptoms before splitting them into two groups: a) taking levacetylleucine for 12 weeks (period 1) followed by placebo pill for 12 weeks (period 2), or b) beginning with the placebo pill for 12 weeks (period 1) and then taking levacetylleucine for 12 weeks (period 2). The researchers performed symptom examinations and conducted interviews to assess quality of life at the midpoint of each period, between period 1 and 2, and at the end of period 2. Importantly, this experimental design allows the researchers to evaluate levacetylleucine’s effects compared to the placebo before, during, and after treatment, all within the same participant.

But what symptoms did the researchers test, and how? The primary clinical outcome in this study was the Scale for the Assessment and Rating of Ataxia (SARA), a clinically gold-standard exam that measures an individual’s motor control through assessments of walking, speech, hand movements, and more. The SARA is scaled from 0 to 40, with a higher score indicating worse ataxia. On this scale a one-point decrease is considered a clinically meaningful improvement. Researchers also assessed subjective impairment and quality of life using a variety of evaluations, including the Clinical Global Impression of Severity (CGI-S) and Improvement Scale which was completed by the investigators, patient caregivers, and the patients themselves. Based off patient symptom improvement by the end of the clinical trial, this evaluation assigns patients a score of one through seven, with one meaning “very much improved” and seven meaning “very much worse”. Both SARA and CGI-S scores were compared between baseline assessments prior to period 1, and after receiving levacetylleucine or placebo. To complement this, patients and their caregivers participated in exit interviews at the completion of the study, providing their perspective on the treatment’s impact on their quality of life. Throughout the study, researchers monitored various health events, including infections, gastrointestinal issues, and respiratory complications that emerged or worsened during the trial to evaluate the safety of levacetylleucine consumption.

Levacetylleucine keeps ataxia on its toes

Levacetylleucine treatment showed promising results across the 70 ataxia-telangiectasia patients that completed the study. 12-week levacetylleucine administration reduced SARA scores by an average of 1.92, while placebo produced negligible changes, indicating that the drug’s effects were real. Interestingly, patients that received levacetylleucine in period 1 and then placebo in period 2 showed a relapse of ataxia in period 2 as the drug’s effects diminished over time. This finding solidifies that ataxia improvements in this patient cohort are driven by the effects of levacetylleucine. The implications of these ataxia improvements were demonstrated by improved CGI-S scores- meaning greater perceived improvement in quality of life- during levacetylleucine administration relative to placebo. Similarly, in other quality of life examinations, adult patients reported that the drug reduced incidence of severe mobility issues, decreased pain and discomfort, and improved their ability to do usual activities. These reports were inverse during placebo administration, with patients reporting more issues with mobility, pain, and daily functioning. During exit interviews, 81% of patients or caregivers reported that levacetylleucine produced meaningful improvements in their symptoms. 66% of these respondents agreed that the drug not only improved the patients’ lives but had beneficial effects for their caregivers as well. Additionally, levacetylleucine had a strong safety profile during the trial, as less than 10% of patients experienced treatment-related adverse events. None of these events were serious concerns to patient health, showing the drug was well-tolerated.

A step forward for individuals with ataxia-telangiectasia

This study is the first phase three clinical trial completed for an ataxia-telangiectasia therapeutic. Levacetylleucine’s benefits for ataxia and quality of life establishes this drug as a potential future treatment for this patient population. Further, these findings support the potential use of levacetylleucine in other neurodegenerative diseases that affect neuronal energy production. There is an ongoing open-label extension phase of this trial in which researchers are further investigating the long-term and disease-improving effects of this drug on patients with ataxia-telangiectasia, so more work is still needed until levacetylleucine can truly start improving the lives of individuals living with this disease. There are a few notable limitations to this work. First, this study excluded patients younger than 4 years old, asymptomatic, and at advanced disease stages, prohibiting the researchers from assessing the therapeutic effects of levacetylleucine in these specific disease contexts. The researchers also did not incorporate a study timeline long enough to evaluate levacetylleucine’s potential effects on the immune system or cancer risk, which are large concerns in ataxia-telangiectasia. Finally, ataxia-telangiectasia is known to have damaging effects on peripheral nerves, causing loss of reflexes and numbness in the limbs. However, the treatment’s ability to alleviate these symptoms was not examined in this study. Overall, this clinical trial found that 12 weeks of levacetylleucine administration improved motor control and quality of life in patients with ataxia-telangiectasia, a rare and fatal neurodegenerative disease with no FDA-approved treatment. The drug reduced ataxia severity compared to placebo, produced few adverse side effects, and may offer a promising future therapy, though further research is still needed.

Key Words

Ataxia: a disease symptom associated with a lack of voluntary coordination in muscle movements, often caused by damage to the cerebellum.

SARA: Scale for the Assessment and Rating of Ataxia, an examination used by clinicians to quantify the extent of an individual’s ataxia by testing gait, stance, sitting, speech disturbances, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide

Clinical Global Impression of Severity (CGI-S) and Improvement Scale: A one – seven scoring scale that determines subjective perception of symptom improvement after receiving a treatment, with one indicating great improvement and seven indicating severe worsening.

Conflict of Interest Statement

The author and editor have no conflicts of interest to declare.

Citation of Article Reviewed

Martakis, K., et al., Safety and efficacy of levacetylleucine in ataxia telangiectasia: a phase 3, randomized, double-blind, placebo-controlled crossover trial. Lancet Neurology., 2026. 25(7): 633-44. (https://pubmed.ncbi.nlm.nih.gov/42309084/)