Dexpramipexole is an investigational drug that has been the subject of research to understand its potential therapeutic applications, particularly in neurodegenerative diseases.
What is Dexpramipexole
Dexpramipexole is a synthetic small molecule, specifically the R(+) enantiomer of pramipexole, a benzothiazole derivative. As an investigational drug, it is not approved for general clinical use.
This orally bioavailable and water-soluble compound exhibits linear pharmacokinetics and dose proportionality. It differentiates from its S(-) enantiomer, pramipexole, which is an approved drug for Parkinson’s disease.
How Dexpramipexole Works
Dexpramipexole’s proposed mechanism of action centers on its neuroprotective properties, primarily by enhancing mitochondrial function. Mitochondria are the cellular powerhouses, and their dysfunction is a common feature in many neurodegenerative conditions. By improving mitochondrial efficiency, dexpramipexole helps reduce oxidative stress and cellular damage.
The drug is thought to protect motor neurons and other brain cells from damage. It also appears to reduce apoptosis, or programmed cell death, which contributes to neuron loss in neurodegenerative diseases. These actions suggest dexpramipexole works by maintaining mitochondrial health in conditions characterized by neuronal death.
Dexpramipexole in Disease Treatment
Dexpramipexole has been investigated for its potential in treating Amyotrophic Lateral Sclerosis (ALS), a rapidly progressive neurodegenerative disorder. ALS leads to muscle weakness, atrophy, and ultimately respiratory failure due to the progressive loss of motor neurons in the brain and spinal cord. Its investigation in ALS stems from its neuroprotective actions, targeting mitochondrial dysfunction, oxidative stress, and inflammation.
While ALS has been the primary focus, dexpramipexole has also been explored for other neurodegenerative conditions. These diseases often share common pathological features, such as mitochondrial impairment and neuroinflammation, making them potential targets for drugs with similar mechanisms of action. The drug also decreased eosinophil counts in an ALS trial, leading to its investigation in hypereosinophilic syndromes and eosinophilic asthma.
Clinical Trial Outcomes and Regulatory Status
The most significant clinical investigation of dexpramipexole for ALS was the Phase 3 EMPOWER trial. This randomized, double-blind, placebo-controlled study enrolled 943 participants with ALS across 81 sites in 11 countries. Patients received either 150 mg of dexpramipexole twice daily or a placebo for 12 to 18 months.
The primary endpoint of the EMPOWER trial was a joint rank analysis of function and survival, known as the Combined Assessment of Function and Survival (CAFS) score. The trial did not meet this primary endpoint, and no efficacy was observed in the individual components of function or survival. At 12 months, there were no significant differences in the mean change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score or in time to death between the dexpramipexole and placebo groups.
Based on these results, Biogen Idec, one of the developers, discontinued the development of dexpramipexole for ALS. Dexpramipexole is not approved by the U.S. Food and Drug Administration (FDA) or other major regulatory bodies for the treatment of ALS.
Potential Adverse Effects
In clinical trials, dexpramipexole was generally well-tolerated, though some adverse effects were reported. Common side effects included gastrointestinal issues, fatigue, and dizziness.
Neutropenia, a reduction in a type of white blood cell, was noted in a subset of participants in the Phase 3 ALS trial, occurring in 8% of the dexpramipexole group compared to 2% in the placebo group. Most adverse events were mild to moderate in severity and rarely led to discontinuation of the study drug.