Pridopidine (Huntexil, ACR-16)

Dopamine in the HD Brain^

The brain plays a delicate balancing act: it needs to maintain the right levels of many brain chemicals in order to orchestrate movements and execute thoughts. In people with Huntington’s disease (HD), that balance is threatened; the brain has trouble regulating neurotransmitters, chemicals in the brain that transfer messages between neurons. This causes miscommunication between different parts of the brain. As a result, people with HD have less control over behaviors and movements that are usually directed by the affected neurotransmitters, as described in greater detail here. Pridopidine, which is being investigated as a treatment for the motor symptoms of HD, is thought to restore the balance of neurotransmitters that the brain needs to function.

Specifically, pridopidine is believed to work by stabilizing levels of the neurotransmitter dopamine in the brain. Dopamine has a number of different roles depending on what part of the brain it acts on, but in the HD brain, the most relevant function is its effects on motion. Dopamine in the striatum, a part of the brain responsible for planning and controlling movements, helps coordinate voluntary motions (like walking or waving) and prevent involuntary motions (like the unwanted dance-like movements of chorea), as discussed in more detail here.

However, sometimes there’s too much of a good thing. When there’s too much dopamine in certain parts of the striatum, the brain has trouble stopping involuntary movements, which causes chorea. On the other hand, when there’s too little, the brain can’t start voluntary movements, and the symptoms – such as stiffness, staggering, and difficulties speaking – get in the way of everyday life. The brain walks a tightrope as it tries to maintain the right balance of neurotransmitters, and the slightest disturbance can cause movements to falter (Andre et al., 2011).

How Pridopidine Works^

As a dopamine stabilizer, pridopidine is thought to reduce the effects of dopamine when there’s too much, and increase its effects when there’s too little. When dopamine levels are too high, pridopidine interacts with dopamine receptors, which act as the “ears” the neuron uses to “hear” dopamine. These receptors have a very specific shape that allows them to bind and recognize dopamine, and when levels of dopamine are high, the receptors change shape as they become more active. Pridopidine is particularly attracted to the “active” form of the receptor and lodges itself in the spot where dopamine usually binds, preventing dopamine from interacting with the receptor. In this way, pridopidine blocks the dopamine receptor from sensing and responding to dopamine when dopamine levels are too high (Pontel et al., 2010).

Conversely, when levels of dopamine are low, pridopidine has a round-about way of increasing dopamine production. HD affects more than just dopamine: low levels of the neurotransmitter glutamate in a region of the brain called the cortex  are also associated with the disease (Pontel et al., 2010). The cortex is the part of our brain that helps us think and plan, and tells the striatum what voluntary movements to perform. Pridopidine raises glutamate levels in the cortex, allowing it to communicate better with the striatum. This increases dopamine levels in the parts of the striatum that had too little. By increasing glutamate signaling in the cortex, pridopidine increases dopamine levels in certain parts of the striatum, allowing voluntary movements to occur (Andre et al., 2011).

Pridopidine therefore plays two opposing roles in the brain, which stabilize dopamine levels. In this way, pridopidine is thought to help the brain reestablish a normal balance of neurotransmitters, and thus regain control over motion.

Research on HD^

Neurosearch, a pharmaceutical company based in Sweden, has conducted two different clinical trials on pridopidine.

MermaiHD (2009)^

The MermaiHD study was a phase III clinical trial, conducted in 32 centers spread across eight countries in Europe. 437 HD patients were randomly assigned to one of three groups: one treatment group received 45 mg of pridopidine once per day; the second treatment group received 45 mg of pridopidine twice per day; the control group received a placebo. To prevent potential bias, MermaiHD was a double-blind study; neither doctors nor patients knew whether the patient was receiving pridopidine.

After 6 months, patients were given the opportunity to continue participating in the study for another 6 months. In this “open-label” phase, the 357 patients who opted to proceed took 45 mg of pridopidine twice daily – no patients were given placebo. The purpose of the open-label segment of the study was to test whether pridopidine is safe and effective for longer periods of time.

Preliminary results suggest that pridopidine might help HD patients control motor symptoms. Doctors measured patients’ progress using the modified Motor Score (mMS), which tests a patient’s ability to perform voluntary movements. Results suggest that patients taking pridopidine performed better on the mMS; patients taking 45 mg of pridopidine twice daily averaged a 1.0 point improvement on the test. However, the results of the mMS did not reach the goals that the scientists had set out to prove: these results reached a statistical significance level of p=0.042. This means that there is a 4.2% probability that pridopidine is no better than a placebo, and that these results occurred by chance; they had originally aimed for a p=0.025.

However, further data analysis indicates that pridopidine may still hold promise. The mMS is just a subsection of a more widely-used test called the Unified Huntington’s Disease Rating Scale (UHDRS), which is described in more detail here. When measured on the motor category of the UHDRS, a test called the UHDRS-TMS, the results were very significant: Patients taking 45 mg of pridopidine twice per day had a 3.0 point improvement, at a statistical significance level of p=0.004. To put that in perspective, HD patients generally experience a 3-point annual decline in their UHDRS-TMS score. This strongly indicates that pridopidine improves motor symptoms of HD.

Furthermore, pridopidine did not appear to have notable side effects, and didn’t make other symptoms of the disease worse. This was a concern because other treatments, such as tetrabenazine, sometimes cause depression and other side effects if they change neurotransmitters too much in the wrong parts of the brain, as described here.

HART (2010)^

In the HART study, Neurosearch and the Huntington Study Group teamed up to study pridopidine further. The HART study was a phase IIb clinical trial, which measures how well a drug works at the prescribed dose. The study was also conducted to see whether pridopidine is effective and safe, and to establish an optimal dose. HART enrolled 227 patients, and was run in 28 centers across America and Canada. Like the MermaiHD study, the HART study was randomized, double-blind, and placebo-controlled.

To determine the dose, there was one placebo group and three treatment groups; patients received 10 mg, 22.5 mg, or 45 mg of pridopidine twice per day.

After just 12 weeks, a significant effect was seen in the group taking the largest dose, 45 mg. Total motor function, as measured by the UHDRS-TMS, improved by 2.8 points, which was statistically significant with a p=0.039. Again, the original test – the mMS – did not show statistical significance, though it did show a strong trend with p=0.078.

The HART study backed up the findings of the MermaiHD study and also helped scientists determine which dose of pridopidine is most effective. This study will continue in an open-label phase, where patients who participated in HART are given the opportunity to continue taking pridopidine until the U.S. Food and Drug Administration (FDA) decides whether or not to approve pridopidine.

Conclusions^

Pridopidine significantly improves motor function, and has a positive effect on both voluntary and involuntary motor actions. Furthermore, it is very well tolerated, even when patients are taking other drugs, such as antipsychotics. However, pridopidine isn’t a “miracle drug” – while the findings are very hopeful, the drug has only been shown to improve motor symptoms; there is no evidence that it can “cure” the disease. Also, pridopidine’s effects seem to be limited to motor symptoms; patients experienced no significant changes in cognition, mood, or general ability to function in day-to-day life.

Individually, neither MermaiHD nor HART lived up to the original standards the researchers had set out to meet. However, statistical significance was reached when the results of the two studies were combined, and when the UHDRS-TMS was used to evaluate patients. Based on these results, Neurosearch lobbied the FDA, which regulates American drugs, and the European Medicines Agency (EMA), which regulates European drugs, to accept pridopidine as a treatment for HD. However, both organizations have asked for another phase III clinical trial to validate that pridopidine lives up to these promises. Neurosearch has declared that it will carry out a further trial, but has not yet announced further details. If it successfully passes this trial, the FDA and EMA would be likely to allow pridopidine to start being marketed as a treatment for HD.

Bibliography^

1. André VM, Cepeda C, Levine MS. Dopamine and glutamate in Huntington’s disease: A balancing act. CNS Neurosci Ther. 2010 Jun;16(3):163-78. Epub 2010 Apr 8. Review. This article discusses dopamine and glutamate signaling in the brain, and is very technical.
2. Miller, Marsha L. “The American ACR16 Trial Results.” HDAC.org. Huntington’s Disease Advocacy Center, 14 Oct. 2010. Web. 5 July 2011. This article discusses the MermaiHD and HART studies, and is moderately difficult.
3. Ponten H, Kullingsjö J, Lagerkvist S, Martin P, Pettersson F, Sonesson C, Waters S, Waters N. In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol. 2010 Oct 10;644(1-3):88-95. Epub 2010 Jul 24. This highly technical article discusses how Pridopidine is believed to work in the brain.