Huntexil (pridopidine)

Huntexil&reg; (pridopidine; (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride; NeuroSearch A/S) belongs to a new class of agents known as dopaminergic stabilizers, which act on the central nervous system. These compounds counteract the effects of excessive or insufficient dopaminergic transmission and may therefore have a therapeutic application in neurological and psychiatric disorders characterized by altered dopaminergic transmission, such as Huntington’s disease (HD).

Huntexil is in late-stage development as a treatment for HD. In February 2010, NeuroSearch announced positive results from the largest European phase 3 study in HD carried out to date (MermaiHD – see later). The MermaiHD study examined the effects of Huntexil in patients with HD and the results show that after 6 months of treatment, Huntexil significantly improves motor function, and has positive effects on both voluntary and involuntary motor symptoms. Huntexil is very well tolerated and has an adverse event profile similar to placebo.



Systematic (IUPAC) name:

4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride Chemical data:

Formula: C15H23NO2S.HCl

Molecular weight: 317.87

Intellectual property
Huntexil and its use and synthesis are protected by a comprehensive patent portfolio for which NeuroSearch holds all rights. The composition-of-matter is protected by patents or patent applications covering more than 50 countries. Pending successful examination and any exclusivity extensions, the composition-of-matter patent runs until at least 2026. The patent applications also cover other proprietary compounds in the NeuroSearch portfolio of dopaminergic stabilizers. In March 2010, NeuroSearch filed an additional patent application to cover the ability of Huntexil to slow down disease progression in symptomatic patients with HD as well preventing onset of symptoms in pre-manifest patients.

Dopaminergic stabilizers
Dopaminergic stabilizers are a new class of compounds that can enhance or counteract dopaminergic effects in the central nervous system. They have a dual mechanism of action, displaying functional antagonism of subcortical dopamine type 2 (D2) receptors as well as strengthening of cortical glutamate transmission. Dopaminergic stabilizers are therefore able to regulate both hypoactive and hyperactive functioning in areas of the brain that receive dopaminergic input (i.e. cortical and subcortical regions). This potential ability to restore the cortical–subcortical circuitry to normal suggests that dopaminergic stabilizers may be able to improve symptoms associated with several neurological and psychiatric disorders, including HD.

Pharmacology of Huntexil
In vitro studies demonstrate that Huntexil exerts its effects by functional antagonism of D2 receptors. However, Huntexil possesses a number of characteristics     that differentiate it from traditional D2 receptor antagonists (agents that block receptor responses).
 * Lower affinity for D2 receptors than traditional D2 ligands.
 * Preferential binding to activated D2 (D2high) receptors (i.e. dopamine-bound D2 receptors).
 * Rapid dissociation (fast ‘off-rate’) from D2 receptors.
 * D2 receptor antagonism that is surmountable by dopamine.
 * Rapid recovery of D2-receptor-mediated responses after washout.

Unlike dopamine antagonists (such as antipsychotics), Huntexil is not expected to produce extrapyramidal symptoms, such as akinesia (inability to initiate movement) and akathisia (inability to remain motionless). Furthermore, Huntexil displays no detectable intrinsic activity, differentiating it from D2 receptor agonists and partial agonists (agents that stimulate receptor responses). Huntexil therefore differs from D2 receptor antagonists, agonists and partial agonists.

As a dopaminergic stabilizer, Huntexil can be considered to be a dual-acting agent, displaying functional antagonism of subcortical dopaminergic transmission and strengthening of cortical glutamate transmission.
 * In vivo, Huntexil interacts with D2 receptors and increases striatal levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid.
 * In vivo, Huntexil increases cortical expression of the gene encoding activity-regulated cytoskeletal protein (Arc) and reverses perturbed behavioural patterns in hypoglutamatergic states (MK-801-induced hyperactivity models).

Huntexil clinical development programme
MermaiHD study

NeuroSearch has recently completed the largest European HD trial to date, the MermaiHD study (Multinational EuRopean Multicentre ACR16 study In Huntington’s Disease).

This 6-month, phase 3, randomized, double-blind, placebo-controlled trial recruited patients from Austria, Belgium, France, Germany, Italy, Portugal, Spain and the UK, and compared two different pridopidine dose regimens with placebo. Patients were randomly allocated to receive Huntexil 45 mg once daily, 45 mg twice daily or placebo. During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two doses (one morning and one afternoon dose) until the end of the treatment period. The study had a target recruitment of 420 patients; recruitment was finalized in April 2009 with 437 patients enrolled.

The purpose of the study was to assess the effects of Huntexil on voluntary motor function (i.e. movements that a person has voluntary control over), which was measured using a scale called the modified motor score (mMS). The mMS comprises 10 items relating to voluntary motor function from the Unified Huntington’s Disease Rating Scale (UHDRS).

After 6 months of treatment, patients who received Huntexil 45 mg twice daily showed statistically and clinically significant improvements in both voluntary and involuntary motor function compared with placebo. Huntexil was also very well tolerated, had an adverse event profile similar to placebo and gave no indication of treatment-associated worsening of symptoms.

In patients who did not receive Huntexil (the placebo group), there was a strong correlation between the length of the HD gene and the rate of motor symptom progression. This is in agreement with findings that suggest that the greater the number of CAG repeats in the HD gene, the faster symptoms progress. In the MermaiHD study, patients who received Huntexil showed no apparent CAG-dependent progression of motor symptoms, suggesting that Huntexil could potentially modify HD progression.

MermaiHD study – open-label extension

Patients who completed the 6-month randomized phase of the MermaiHD study could choose to enter a 6-month, open-label extension. The majority of patients have decided to continue treatment in the extension study. Results are expected to be available in the second half of 2010.

HART

NeuroSearch is conducting a 3-month, phase 2b, randomized, double-blind, placebo-controlled study in Canada and the USA – HART (Huntington’s disease ACR16 Randomized Trial). This study has a target recruitment of 220 patients and is due to complete towards the end of 2010. Patients are randomly allocated to receive Huntexil 10 mg, 22.5 mg or 45 mg twice daily, or placebo. During weeks 1–4, patients receive once-daily treatment (as a morning dose). Thereafter, patients take two treatment doses (one morning and one afternoon dose) until the end of the treatment period.

Compassionate use programme

In order to meet requests from patients and healthcare professionals for continued treatment with Huntexil, NeuroSearch will offer patients who complete the MermaiHD study further treatment under an open-label compassionate use programme (if requested by their treating physician and only if permission is obtained from the relevant local authorities).

Euro-HDB study

NeuroSearch is also supporting a large European study assessing the burden of HD for patients and their carers (Euro-HDB). In Euro-HDB, the Huntingdon Self-Assessment Instrument (HSAI) has been devised as a unique tool to capture information about the socioeconomic burden of HD. These results should guide the development of appropriate policies for the management of this complex condition.