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BOSTON -- It's unclear whether pridopidine, an investigational drug targeting the sigma-1 receptor, has a future in treating Huntington's disease (HD) after a phase III trial failed to deliver a clearly favorable verdict, according to new data presented here.

In the so-called , patients receiving pridopidine did not achieve better scores on the Unified Huntington's Disease Rating Scale's total functional capacity (UHDRS-TFC) evaluation after 65 weeks compared with a placebo group, according to Andrew Feigin, MD, of New York University in New York City. Change from baseline in UHDRS-TFC score was the trial's primary endpoint.

With scores averaging about 9.9 at enrollment in the two arms, both groups saw declines of 1 point during the study, Feigin reported at the American Academy of Neurology annual meeting.

He did see glimmers of hope in other outcomes, however. No adverse effects of concern were seen in the 499-patient study, and only 15% of participants stopped their assigned agent or were lost to follow-up. Moreover, some efficacy measures did suggest a benefit, albeit with uncertain durability.

The drug's Netherlands-based developer, Prilenia Therapeutics, thought pridopidine had a good chance of passing the phase III test. It whose activation serves to boost neuronal health and function, while exerting no activity at dopamine D2/3 receptors that would otherwise lead to side effects. Prilenia sees potential for the agent in several nerve disorders; besides HD, clinical testing in amyotrophic lateral sclerosis (ALS) is underway, and the Parkinson's disease, neurodegenerative eye disease, and Rett syndrome, among others, for additional trials.

An earlier trial had suggested that HD patients taking so-called neuroleptic drugs, as well as those using currently approved drugs for HD such as tetrabenazine (Xenazine), may respond less well to pridopidine. Because these treatments are common in HD, the PROOF-HD team didn't want to exclude them. They did, however, want to be sure that the active-drug and placebo arms had similar numbers of such patients, to avoid imbalances that could confound the analyses.

The 499 patients were randomized 1:1 to pridopidine or placebo, with separate randomization for those using neuroleptics and anti-chorea medications. Mean disease duration was about 4.5 years; some 60% were classed as stage 2 and 40% as stage 1. Just over 40% of patients in the two arms were using neuroleptics; despite the effort to keep the same balance for anti-chorea drugs, these were used in 19% of the placebo group and 28% of those assigned to pridopidine.

The new results (Feigin noted that they were extremely fresh -- data were unblinded only 2 weeks ago) supported the earlier findings of a difference in response. Whereas UHDRS-TFC scores showed nearly identical declining trajectories in the two arms across the entire sample, taking patients using neuroleptics and/or anti-chorea medications out of the analysis suggested that pridopidine did have some protective effect. Yet even this difference did not persist for the full 65 weeks, because mean scores at that point were the same with pridopidine and placebo.

But Feigin was encouraged by results on another efficacy measure, the . By this measure, pridopidine was significantly better than placebo when assessed at week 26 and remained numerically superior out to week 65. And with participants on neuroleptics and/or anti-chorea drugs removed, pridopidine significantly outperformed placebo throughout the entire study.

Nevertheless, to the extent that the data suggested a benefit with pridopidine, it appeared to peak in the first 6 months and then fade away. Q-Motor scores with neuroleptic/anti-chorea drug users excluded increased by about 20 points initially while those in the placebo group declined -- but the gap then shrank with further treatment. Other secondary efficacy measures examining cognition, for example, showed the same pattern.

Feigin emphasized that further analyses were forthcoming. For its part, Prilenia has made no announcement about its plans for pridopidine, perhaps awaiting the outcome of those additional analyses. An open-label extension is also underway, which includes 97% of the 437 patients who were still in the trial and on their originally assigned treatments at week 65.

A separate presentation at the same AAN session also touched on pridopidine. It's one of seven agents now being tested in a so-called . Preliminary results from the first four of these drugs were reported by Sabrina Paganoni, MD, PhD, of Massachusetts General Hospital in Boston, including pridopidine.

All agents in this phase II study are being tested under the same protocol and with the same endpoints, the primary being 24-week change in a standard evaluation of overall ALS severity. As in PROOF-HD, this endpoint was missed. But also as in PROOF-HD, there were indications of benefit in other measures, including "stronger effects" among patients less than 18 months from diagnosis and those with relatively mild symptoms. Also, among "fast-progressing" patients, those on the drug had lower levels of neurofilament light, a key biomarker of neuronal degradation. Paganoni said her group had recommended a larger study of pridopidine for ALS.

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