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The application is based on results of Prilenia Therapeutics’ phase 3 study that assessed the safety and efficacy of pridopidine in patients with Huntington disease.
Ralf Reilmann, MD
(Credit: George-Huntington-Institute)
According to a new announcement, the European Medicines Agency (EMA) accepted the marketing authorization application (MAA) for Prilenia Therapeutics’ pridopidine, a highly selective and potent sigma-1 receptor (S1R) agonist, for the treatment of adults with Huntington disease (HD).1 If approved, it could be the first treatment with the ability to impact progression in patients with HD and would be available as early as the second half of 2025.
The MAA application is based on the totality of safety and efficacy evidence from the HD agent’s extensive development program, such as observed in the phase 3 PROOF-HD trial (NCT04556656). Reviewing the MAA can typically take up to between 12 to 14 months, but it can take even longer sometimes. The company noted in the announcement that while MAA is reviewed, it will continue conversation with the FDA on a potential path forward for pridopidine in the United States. Prilenia also noted that it will consider regulatory submissions for other countries and regions after the regulatory review process in Europe.
“HD is a genetic, rare, fatal neurodegenerative disease that remains without any approved therapeutic options capable of impacting the progression of the disease. All we have to give patients right now is a small handful of options that may offer some degree of symptom control for HD-related chorea and behavioral complications,” Ralf Reilmann, MD, neurologist and founding director of the George-Huntington-Institute in Muenster, Germany, said in a statement.1
Analyses from the phase 3 PROOF-HD trial presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, showed that pridopidine significantly improved or stabilized outcome measures for at least 1 year and displayed superiority against placebo for up to 78 weeks on all end points after excluding patients on antidopaminergic medication (ADMs).2,3 These findings suggested that pridopidine still maintained benefit on several clinical measures of disease progression in patients with HD without the help of these therapies.
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“Patients deserve better than to slowly and inexorably decline from this devastating disease, and this could be the biggest advance in therapy in years. Pridopidine could, for the first time, provide an option that may slow down decline in several functionally relevant disease domains and thus potentially offer patients and their families an extension to the quality time they have together. Since its safety profile appears favorable and it is taken orally, pridopidine can be easily made available to patients,” Reilmann added in a statement.1
Excluding participants on ADMs (pridopidine, n = 79; placebo, n = 99), pridopidine-treated patients showed improvement from baseline on the Unified Huntington Disease Rating Scale (cUHDRS) up to week 52 and sustained benefit up to week 78 compared with placebo. Similarly, quantitative motor (Q-Motor) and Stroop Word Reading (SWR) improved from baseline at week 26 and sustained up to week 78 in comparison with the placebo. In addition, investigators observed a trend for improvement in Quality of Life (HD-QoL) also in this group of patients.
Presented by lead author Michal Geva, PhD, senior vice president, head of research, Prilenia Therapeutics, and colleagues, PROOF-HD enrolled 499 patients with onset HD who had a Total Functional Capacity (TFC) scale score of at least 7. In the trial, the primary end point was the change from baseline to week 65 in TFC with key secondary end point that included change from baseline in the composite cUHDRS, a combined measure of motor function, cognition, and functional capacity. Additional end points investigators included were Q-Motor, cognition (SWR), and HD-QoL. The prespecified analyses excluded participants who had ADMs, including neuroleptics and antichorea medications, as their use may be associated with a worsening of disease progression.
“We have studied pridopidine extensively and have a clear understanding of its efficacy and safety. Pridopidine has delivered consistent efficacy benefits across multiple key measures of HD and has demonstrated a placebo-like safety profile in a large safety database,” Michael Hayden, MBChB, PhD, CEO at Prilenia, said in a statement.1 “We have submitted a compelling suite of evidence and pridopidine presents the opportunity for a much-needed paradigm shift in HD therapy.”
A responder analysis of patients without ADMs revealed that pridopidine enhanced responder rates (5% improvement as threshold) across all visits for multiple key end points including cUHDRS, SWR, and Q-Motor. Thus, this analysis suggests that pridopidine demonstrated consistent and clinically meaningful separation of pridopidine at all timepoints and for key outcome measures. Overall, pridopidine was well tolerated with a safety profile comparable with placebo.
“People with HD are acutely aware of their need for new and better treatment options, especially those that can slow down decline,” Astri Arnesen, president of the European Huntington's Association, said in a statement.1 “Complex and rare diseases, like HD, are highly challenging and require forward-thinking, and we applaud the progress regulators are making in trying to support the urgent needs of people with HD. If we can come out of the other end of this process with a new therapeutic approach, offering the potential to slow down disease progression, we will have taken a huge step forward for the whole community.”
