Has Pridopidine Run Its Course in Huntington Disease?

Ralf Reilmann, MD

Newly published phase 2 results have shown that pridopidine (Huntexil, Teva) may ultimately be unable to improve motor function in patients with Huntington disease, adding to the list of negative trials for the therapy.¹

The findings of the PRIDE-HD study—some of which were originally presented at the American Academy of Neurology’s 2017 annual meeting—have shown that pridopidine did not improve patients’ Unified Huntington's Disease Rating Scale total motor scores (UHDRS-TMS) after 26 weeks in comparison with placebo.

The trial included 397 patients in the final analysis and, ultimately, this lack of significant difference was true for all doses—45 mg (n = 75), 67.5 mg (n = 79), 90 mg (n = 81), and 112.5 mg (n = 81) twice daily—compared to placebo (n = 81).

As a result, Ralf Reilmann, MD, of the George Huntington Institute, and coauthors noted that the findings of secondary or tertiary analyses in previous trials were not replicated in PRIDE-HD. However, they wrote that “a potentially strong placebo effect needs to be ruled out in future studies.”

Although, whether or not future studies will be conducted with the therapy, previously known as ACR16 and ASP2314, remains to be seen. The findings of PRIDE-HD mark the third clinical trial and second phase 2 study to report negative results with pridopidine in Huntington.

Previously, the therapy was tested in the phase 2b HART trial (NCT00724048), which failed to show symptom improvement across doses of 20 mg, 45 mg, and 90 mg despite being well-tolerated. As well, the phase 3 MermaiHD trial (NCT00665223), conducted in Europe, showed similar results for 437 patients randomized to either 45 mg pridopidine, 90 mg pridopidine, or placebo.

The results of both the HART and MermaiHD trials were presented to the FDA in March 2011, though the agency noted that there was insufficient evidence to allow approval in human patients, and a further phase 3 trial would be required for approval.²

Despite these failures, in February 2018, Waters et al. published an overview of pridopidine’s pharmacology and rationale for use in Huntington disease, noting that “preclinical pharmacology data on pridopidine demonstrate balancing effects on motor function through the dopamine system, and indirect enhancement of cortico-striatal synaptic activity,” which could imply potential to improve the negative motor features of the disease.³

They explained that in addition to the indirect and direct effects of the therapy on dopamine signaling, emerging evidence has suggested the possibility of “a role for sigma-1 receptor interactions and regulation of calcium signaling contributing to potential disease-modifying effects of pridopidine.”

“Mechanistic studies specifically testing these hypotheses could be performed in animal models of HD. In addition, further human studies are warranted to investigate whether pridopidine may modify HD progression rate or prolong the time to phenoconversion in HD gene carriers,” Waters and colleagues wrote.

Although, just a few months later, in May 2018, the therapy’s manufacturer, Teva Pharmaceuticals, announced that it had entered an agreement with NeuroSearch, the company from which Teva had acquired the rights to develop pridopidine. The agreement stated that in the event that Teva “entered into an agreement with an identified third party relating to the sale and transfer of Teva's rights in and to pridopidine,” prior to October 31, 2018, then it would pay NeuroSearch $450,000.⁴

This agreement was reached, according to Teva, due to its decision to halt development of the therapy following its third failure in the phase 2 PRIDE-HD trial, and “potential interest in the asset by an identified third party.”

Despite Teva’s announcement of ceased development, in August 2018, Grand View Research published a report on the Huntington disease market trends, which noted that pridopidine is expected to be the only new symptom-alleviating drug to be launched during the forecast period of 2018 to 2023.⁵ As the dopidine class of medications, of which pridopidine is a member, is relatively new, the future of the therapy’s growth remains uncertain.

REFERENCES

1. Reilmann R, McGarry A, Grachev ID, et al. Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. epub December 15, 2018. thelancet.com/journals/laneur/article/PIIS1474-4422(18)30391-0/fulltext. Accessed December 18, 2018.

2. NeuroSearch provides an update on the development plan for Huntexil® in the treatment of Huntington's disease following the End of Phase II meeting with the FDA [press release]. Hvidovre, Denmark: NeuroSearch; Published March 23, 2011. neurosearch.com/Default.aspx?ID=8127#_206771. Accessed December 18, 2018.

3. Waters S, Tedroff J, Ponten H, Klamer D, Sonesson C, Waters N. Pridopidine: overview of pharmacology and rationale for its use in Huntington’s disease. J Huntingtons Dis. 2018;7(1):1-16. doi: 10.3233/JHD-170267

4. NeuroSearch and Teva Pharmaceutical International enter into agreement on outstanding obligations [press release]. Hvidovre, Denmark: NeuroSearch; Published May 16, 2018. globenewswire.com/news-release/2018/05/16/1507654/0/en/NeuroSearch-and-Teva-Pharmaceutical-International-enter-into-agreement-on-outstanding-obligations.html. Accessed December 18, 2018.

5. Huntington's Disease Treatment Market Research, 2018 - Analysis By Treatment (Symptomatic Therapy, Disease-modifying Therapy) & Major Markets [press release]. Dublin, Ireland: ResearchAndMarkets.com; Published November 9, 2018. globenewswire.com/news-release/2018/11/09/1648828/0/en/Huntington-s-Disease-Treatment-Market-Research-2018-Analysis-By-Treatment-Symptomatic-Therapy-Disease-modifying-Therapy-Major-Markets.html. Accessed December 18, 2018.