PRidopidine Outcome On Function in Huntington Disease (PROOF-HD)

FREQUENTLY ASKED QUESTIONS (FAQs)

What is pridopidine?

Pridopidine is a small molecule developed by Prilenia for the treatment of neurodegenerative disorders such as HD. Pridopidine binds and activates the Sigma-1 receptor (S1R), a protein that is expressed at high levels within the brain. The S1R regulates key cellular pathways, commonly impaired in neurodegeneration.1

Pridopidine, by activation of the S1R, demonstrates beneficial effects in numerous cellular and animal models of HD. For example, pridopidine rescues neurons from mutant Huntingtin (mHTT) induced cell death in HD patient-derived induced Pluripotent Stem Cells (iPSCs) and in mouse HD neurons.2 Furthermore, HD mice treated with pridopidine show improvement in multiple behavioral and motor functions. 6,7

Have other clinical trials evaluated pridopidine?

In a recently completed clinical study in HD (PRIDE-HD), participants receiving pridopidine dose of 45 mg twice daily, showed maintenance of functional capacity compared to patients receiving placebo, at 52 weeks. This was measured by the Unified Huntington Disease Rating Scale (UHDRS)-Total Functional Capacity (TFC).11

The UHDRS-TFC scale is an accepted tool used by clinicians to assess HD disease stage and the level of patient’s functionality. The scale is driven by tasks that have high relevance to HD patients and families and assesses the patient’s ability to work, to manage finances, to manage a home, to manage oneself, and to live independently at home. TFC is most sensitive to evaluate functionality in early HD patients.

In prior studies (HART and MermaiHD) , pridopidine 45 mg twice daily demonstrated beneficial effects on motor function in HD, as measured by the UHDRS- Total Motor Score (TMS).

Extensive safety data from 1334 subjects treated with pridopidine and accumulated to ~1300 subject-years of exposure indicate pridopidine is a safe and well tolerated drug.

Can pridopidine stop or help to maintain function of patients with HD?

Results from prior studies with pridopidine suggest a potential beneficial effect of pridopidine (45 mg twice daily) on maintenance of functional capacity in HD patients. Maintenance of functional capacity is a critical unmet need in the treatment of patients with HD.

There is no guarantee that participation in the current study will help the participant; the participant may receive a placebo treatment.

Is PROOF-HD currently enrolling participants?

Yes. PROOF-HD is actively enrolling approximately 480 patients globally.

Are there specific qualifications or exclusion criteria for this study?

Yes. There are several requirements that a participant should meet to be enrolled in PROOF-HD, including the following:

• Male or female, 25 years of age and older, capable of giving a signed informed consent.
• Have a diagnosis of HD based on clinical features.
• Have confirmed presence of CAG repeats of 36 or greater in the huntingtin gene.
• Must have adult-onset HD with onset of signs and symptoms at, or later than 18 years of age
• Must be willing and able to comply with the study instructions.

There are additional eligibility requirements that the Principal Investigator can explain to you.

Will I receive the study drug (pridopidine) or a placebo?

Eligible participants will be randomly assigned by chance (like the flip of a coin) to receive either pridopidine or placebo. Neither the participant, nor the physician/site staff will know if the patient is receiving pridopidine or placebo (this is called a double-blind study).

Is my consent required for this study?

Yes. All participants must provide informed consent before being screened and participating in the study.

How do I find a study site and enroll?

PROOF-HD is being conducted by Prilenia Therapeutics (“Sponsor”) in partnership with the Huntington Study Group (HSG). PROOF-HD will take place in North America and Europe. Additional location and contact information is available on the PROOF-HD Study Locations page.

References

1 Su T-P, Hayashi T, Maurice T, Buch S, Ruoho AE. The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci [Internet]. 2010;31(12):557–66. Available from: http://dx.doi.org/10.1016/j.tips.2010.08.007

2 Chelsy Eddings, Nicolas Arbez, Sergey Akimov, Michal Geva, Michael Hayden Ross C, Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, et al. Pridopidine Protects Neurons from Mutant-Huntingtin Toxicity via the Sigma-1 Receptor. Neurobiol Dis. 2017;

3 Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol [Internet]. 2009;5(6):311–22. Available from: http://dx.doi.org/10.1038/nrneurol.2009.54

4 Kusumika Gharami, Yuxiang Xie, Juan Ji An, Susumu Tonegawa and BX. Public Access NIH Public Access. 2013;105(2):369–79.

5 Xie Y, Hayden MR, Xu B. BDNF Overexpression in the Forebrain Rescues Huntington’s Disease Phenotypes in YAC128 Mice. J Neurosci [Internet]. 2010;30(44):14708–18. Available from: http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.1637-10.2010

6 Marta Garcia-Miralles 1, Michal Geva, 2 Jing Ying Tan, 1 Nur Amirah Binte Mohammad Yusof 1, Yoonjeong Cha, 3 Rebecca Kusko, 3 Liang Juin Tan, 1 Xiaohong Xu, 1 Iris Grossman 2, Aric Orbach 2, Michael R. Hayden, 1, 2, 4 5, Pouladi1 and MA. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight. 2017;2(23):1–18.

7 Kusko R, Dreymann J, Ross J, Cha Y, Escalante-Chong R, Garcia-Miralles M, et al. Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse. Mol Neurodegener. 2018;13(1):1–15.

8 Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis [Internet]. 2017 Jan [cited 2019 Mar 12];97(Pt A):46–59. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27818324

9 Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, et al. Pridopidine activates neuroprotective pathways impaired in Huntington Disease. Hum Mol Genet [Internet]. 2016 [cited 2019 Mar 12];25(18):3975–87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27466197

10 Smith-dijak AI, Nassrallah W, Zhang L, Geva M, Hayden M, Raymond L. Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons from a Mouse Model of Huntington Disease.

11 Reilmann R, McGarry A, Mendis N, Schubert R, Skitt Z, Slawek J, 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. 2018;18(2):165–76.