Phase 3 Trial of Oral Pridopidine in Early Stage Patients Opening Soon

Prilenia Therapeutics, in partnership with the Huntington Study Group (HSG), has launched the Phase 3 PROOF-HD clinical trial to evaluate the company’s lead experimental oral therapy, pridopidine, in people with early stage Huntington’s disease.

Pridopidine “is a first-in-class [therapy] candidate, with promising previous clinical results and an established safety profile,” Michael R. Hayden, MD, PhD, Prilenia’s CEO, said in a press release.

“Prior trials of pridopidine have suggested that it may maintain functional capacity in early HD [Huntington’s disease] patients,” said Ralf Reilmann, MD, PhD, the trial’s European principal investigator, adding that “PROOF-HD will focus on this potential effect.”

The rationale for the trial (NCT04556656) was recently presented by Georg Bernhard Landwehrmeyer, MD, PhD, chair of the its Safety Monitoring Committee, at the 2020 European Huntington’s Disease Network (EHDN) Bridging Event, held virtually Sept. 11.

Landwehrmeyer, a professor of neurology at the University of Ulm, in Germany, was also involved in previous pridopidine trials.

Pridopidine is a highly selective small molecule that works by binding to and activating the sigma 1 receptor (S1R), a protein that plays a role in several pathways impaired in Huntington’s and other neurodegenerative diseases. By activating S1R, pridopidine is thought to increase the production of brain-derived neurotrophic factor, a protein with neuroprotective effects and whose levels are reduced in Huntington’s patients.

Previously owned by Teva Pharmaceuticals, pridopidine was tested  in Huntington’s patients in Teva-sponsored Phase 2 and 3 trials, with mixed results. While it failed to significantly improve patients’ motor function in these studies, it did improve their functional capacities, as measured through the Unified Huntington’s Disease Rating Scale – Total Functional Capacity (UHDRS-TCF).

The UHDRS-TCF, ranging from 0 (severe disability) to 13 (normal functionality), assesses patients’ capacity to work, handle finances, perform domestic chores and self-care tasks, and to live independently.

In particular, data from the Phase 2 PRIDE-HD trial (NCT02006472) showed that one year of treatment with pridopidine (45 mg given twice a day) significantly prevented functional decline in patients with early stage Huntington’s. Untreated patients at these early disease stages typically show about a one-point annual decline in UHDRS-TFC, Landwehrmeyer said.

Results from a Phase 2 long-term extension study called OPEN-HART (NCT01306929) also supported these benefits, Landwehrmeyer emphasized, as patients treated with 45 mg of pridopidine for five years showed a significantly slower decline in functional capacity than a placebo group of patients from a separate trial called 2CARE (NCT00608881).

Extensive safety data from more than 1,300 people given various daily doses of pridopidine (including 45 mg) also found the therapy has a favorable safety profile and is well tolerated.

These findings suggested a potential long-term clinical benefit of pridopidine in people with early stage Huntington’s disease.

“The question that has emerged … is will the longer-term application of pridopidine translate into clinical benefits?” Landwehrmeyer said during the presentation, noting that the PROOF-HD Phase 3 clinical trial was designed to answer that.

“We are pleased to be partnering with HSG to explore its impact through the PROOF-HD study,” Hayden added.

The multicenter study, expected to start later this year, will evaluate pridopidine’s safety and effectiveness in about 480 people, ages 25 or older, with early stage adult-onset Huntington’s (UHDRS-TFC scores of seven or higher).

Patients will be recruited at about 30 centers across the U.S. and Canada, and another 30 across Europe. This is the result of a HSG partnership with the Clinical Trials Coordination Center at the University of Rochester to help conduct the trial in North America, and with TFS International AB, a clinical research organization, to assist in Europe.

Participants will be randomly assigned to either 45 mg of pridopidine or a placebo capsule, twice a day for up to 78 weeks (about one and a half years).

The trial’s main goal is to assess changes in patients’ functioning, measured through the UHDRS-TFC. Secondary goals include the proportion of patients responding to treatment (no worsening in UHDRS-TFC), and changes in other Huntington’s symptoms and in quality of life.

After completing the trial, patients will have the option of entering an open-label extension study, in which all will be given pridopidine.

“Slowing the decline in functional capacity in HD patients would be a significant advance in HD care,” said Andrew Feigin, MD, the trial’s North American principal investigator and chair of HSG.

The full program of EHDN’s event can be found here, and recorded sessions can be viewed here.

Prilenia is also evaluating the therapeutic potential of pridopidine in people with other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease.