The European Medicines Agency (EMA) is set to review Prilenia Therapeutics' application for pridopidine, an oral therapy intended for adults living with Huntington's disease. This regulatory step follows promising clinical data suggesting the drug's potential to slow the progression of this debilitating neurodegenerative condition.
Mechanism of Action and Clinical Development
Pridopidine is an orally available small molecule that acts as a selective sigma-1 receptor (S1R) agonist. The S1R protein is expressed in the brain and spinal cord and modulates several key cellular pathways vital for nerve cell function and survival, processes often impaired in neurodegenerative diseases like Huntington’s disease. By targeting S1R, pridopidine aims to alleviate disease symptoms and slow its progression.
The application is supported by data from pridopidine’s clinical development program. Michael R. Hayden, PhD, CEO of Prilenia, stated that pridopidine has shown consistent efficacy benefits across multiple key measures of Huntington’s disease and has demonstrated a placebo-like safety profile in a large safety database.
PROOF-HD Trial and Subgroup Analysis
While the Phase 3 PROOF-HD trial (NCT04556656) involving 499 adults with early Huntington’s disease did not meet its primary endpoint of slowing functional decline as measured by the Unified Huntington Disease Rating Scale-Total Functional Capacity score (TFC), subgroup analyses provided crucial insights. These analyses indicated that pridopidine could slow disease progression in patients who were not concurrently taking antipsychotics or medications for chorea, the involuntary, jerky movements characteristic of Huntington’s disease. Benefits were observed across both motor and cognitive measures in this subgroup.
Andrew Feigin of NYU Grossman School of Medicine, the lead North American investigator for PROOF-HD, noted that the subgroup analysis was pre-specified in the trial protocol, acknowledging the challenges of enrolling Huntington's disease patients not already on medication. He presented the results at the 2023 American Academy of Neurology (AAN) annual congress.
Regulatory Pathway and Potential Availability
Following constructive discussions with European regulators, Prilenia is moving forward with the regulatory process. The EMA’s review typically takes 12 to 14 months, suggesting that pridopidine, if approved, could be available to patients in the second half of 2025. Prilenia is also in discussions with the U.S. Food and Drug Administration (FDA) regarding a potential path to market in the United States and is considering regulatory submissions in other countries after the European review is complete.
Pridopidine has been granted orphan drug status in both the European Union and the U.S. for Huntington’s disease and has received fast-track designation in the U.S., which are intended to accelerate the therapy’s clinical development and regulatory review.
Impact on Huntington's Disease Community
Huntington’s disease is a genetic disorder caused by a mutation in the HTT gene, leading to an abnormally long huntingtin protein that forms toxic clumps inside nerve cells, disrupting their function and causing their death. The disease is characterized by motor, psychiatric, and cognitive symptoms. Currently, treatments primarily address the symptoms of the disease.
Astri Arnesen, president of the European Huntington Association, welcomed the EMA’s decision to review the treatment, emphasizing the urgent need for therapies that can slow disease progression. Ralf Reilmann, MD, a neurologist and the founding director of the George-Huntington-Institute in Muenster, Germany, highlighted that pridopidine could potentially slow down decline in several functionally relevant disease domains, offering patients and their families an extension to the quality time they have together.
Prilenia is also exploring pridopidine as a potential treatment for amyotrophic lateral sclerosis (ALS), another progressive neurodegenerative disease.
