The Lighthouse has been following ACR16 since 2005. We provided the first Internet coverage of this promising drug and have been following its progress ever since. The news from Neurosearch that its European study resulted in significant improvement in the voluntary and involuntary movement is exciting. Before considering approval of the drug, the FDA will want to see the results of the U.S. trial which is still enrolling but the European results are a major step on the path to a new treatment for Huntington's Disease.
ACR16 is a small molecule belonging to a pharmacological class called dopamine stabilizers. It can enhance or inhibit activity depending on the initial level. In other words, if dopamine activity levels are too high, ACR-16 can decrease them, but if activity is too low, ACR-16 can increase it. This contrasts with neuroleptics where a reduction in activity of this neurotransmitter occurs, regardless of initial level.
Dopamine is an important neurotransmitter which plays a role in cognition, mood, attention, learning, motor activity, leep, and behavior, so targeting it needs to be done carefully. Dopamine appears to play a role in Huntington’s Disease. Dopamine receptors are progressively reduced with the progression of the disease. In addition, there is some evidence that there is an abnormal sensitivity to dopamine in the medium spiny neurons affected in HD.
ACR-16 appears to work by strengthening cortical control of the basal ganglia. The striatum, which is part of the basal ganglia, is the brain's autopilot. Once we have learned a behavior, we need not give it our full attention. The striatum will control the activity while our cortex is thinking about something else. Once the striatum begins degenerating in HD, the cerebral cortex loses control of the basal ganglia. This is why HD patients have trouble with multitasking.
The trial tested ACR16 for its ability to improve motor symptoms rather than as a disease modifying treatment. That will have to be determined later. We at the Lighthouse approve of Neurosearch's strategy of testing ACR16 as a treatment for symptoms since 1) treatment of symptoms is important for quality of life and 2) the shorter time needed for a trial like this will get treatments to the HD community sooner.
The good news about ACR16 is cause for celebration. Personally, I am ecstatic.
It's not too late to sign up for the U.S. trial. More information about the trial can be found here: Clinicaltrials.gov
A list of participating sites can be found here: Participating sites for HART
Copenhagen, 3 February 2010 – NeuroSearch (NEUR) today reported positive top-line results from the MermaiHD study, the European Phase III study with Huntexil® (pridopidine) in Huntington's disease.
The MermaiHD study met the primary endpoint to show an effect on voluntary motor function. In addition, data from the 437 Huntington patients, who participated in the study (= ITT population) show that six months' (26 weeks) treatment with Huntexil® results in significant improvements in a broader range of voluntary and involuntary motor symptoms associated with the disease. The study was conducted in 32 centers across Europe, and showed a very high compliance with 92% of the patients completing the study and 82% in full compliance with the study.
Treatment with Huntexil® 45 mg BID (twice daily) demonstrated statistically and clinically significant improvements compared to placebo in the ITT population on the following measures of motor symptoms in Huntington's disease. On the primary endpoint on the Modified Motor Score which assesses voluntary motor function, the experimental group receiving 45 mg twice daily improved significantly compared to the placebo group (p <.02).
The Modified Motor Scale is part of the Total Motor Scale which is the motor part of the Unified Huntington's Disease Rating Scale (the UHDRS), a standard assessment of the disease's effects on movement, including both voluntary and involuntary motor symptoms. The experimental group receiving 45 mg twice daily improved significantly compared to the placebo group (p <.001).
The experimental group receiving the higher dosage also improved on dystonia (prolonged muscle contraction resulting in twisting body motions) which is also measured in the TMS (p < .001). They also improved in voluntary eye movements which is not part of the TMS (p < .002)
Treatment with Huntexil® 45 mg QD (once daily) showed some improvements on these motor function domains, however the improvements at this lower dosage did not reach statistical significance.
The improvements in motor function observed with Huntexil® 45 mg twice daily in the MermaiHD study appear very robust, as they (1) remain consistent across assessments and analyses, (2) show increasing separation from placebo over time, and (3) are consistent also across the two pre-stratified study groups of patients on use/non-use of antipsychotic medication; approximately 40% of patients were on antipsychotics. The importance of studying both patient groups has been emphasized by experts and regulators to demonstrate that Huntexil® improves the symptoms of Huntington's disease per se, and that it is also safe in patients treated with antipsychotics. The use of antipsychotics showed no influence on the positive treatment effects of Huntexil®.
In the study, Huntexil® was generally very well tolerated with an adverse event profile similar to placebo, and the results show no indication that treatment with Huntexil® would be associated with worsening of disease signs and symptoms.
Following the results, NeuroSearch is now initiating interactions with scientific advisors and regulatory agencies (EMEA and FDA) to discuss the MermaiHD study outcome and the plans for submissions for market authorisation for Huntexil® as a novel treatment for Huntington's disease.
Principal investigator, Prof. Justo García de Yébenes, Hospital Ramon y Cajal, Madrid, Spain, commented, "Huntington's disease is a progressive disorder with motor, cognitive, and behavioral symptoms. Huntexil® is the first medication to have demonstrated an overall improvement of the motor impairment in Huntington patients with no worsening of other signs or symptoms and without compromising patient safety. Overall, the MermaiHD study results show that Huntexil® has a favorable clinical risk/benefit profile, and I believe it could be useful to many of my patients."
Chairman of the European Huntington's Disease Network, EHDN, Prof. G.B. Landwehrmeyer, commented, ""The EHDN is very proud to have been part of making the MermaiHD study a success both in terms of quality and time. With more than 400 patients participating, the trial is one of the largest so far conducted in Huntington's disease in Europe, and recruitment was completed within one year. I would like to thank all participants and their caregivers, all investigators and their staff as well as the employees at the EHDN for their dedicated contribution to this achievement."
Flemming Pedersen, CEO of NeuroSearch, commented, "The Phase III results from the MermaiHD study are very encouraging, demonstrating that Huntexil® can provide significant benefits to Huntington patients on symptoms not reached by any current treatment, and this without any "trade-offs" in terms of safety or worsening of any other disease symptoms. We remain determined to bring Huntexil® forward as a new medication to patients with Huntington's disease and we will work closely with physicians and regulatory authorities to make this happen as soon as possible."
NeuroSearch is also evaluating Huntexil® in a second randomised and placebo-controlled study, the HART study, conducted in the USA and Canada and in approximately 220 patients with Huntington's disease. Patient recruitment in the HART study is still ongoing, and study results are expected in the second half of 2010.
Also, the MermaiHD study is followed by an open-label treatment period, which is still ongoing. Patients, who completed the six months' randomised study treatment, have been offered to continue open-label treatment with up to 45 mg Huntexil® twice daily for six months. Close to 90% of the patients have chosen to continue treatment in the open-label phase, and the last patient is expected to complete the full 12 months treatment period in May 2010. Results from the open-label treatment period are also expected to be available in the second half of 2010.