Following are excerpts from HDSA's research newsletter, Toward a Cure. To receive a complimentary copy with the full articles or to be added to the national mailing list, please e-mail Anita Mark-Paul amarkpau@hdsa.org.

Amarin Corporation Announces Results of Potential Treatment for Huntington's Disease

Amarin Corporation recently announced the results of the initial Phase Three clinical trial that was conducted in 2002 by Laxdale Limited for Miraxion™(formerly LAX-101) as a potential treatment for Huntington's Disease.

In their press release dated August 24, 2004, Amarin Corporation stated that a group of patients with a "specific gene variant" experienced a significant response to Miraxion™. The Initial Phase Three trial involved 135 patients at six centers in the United States, Canada and Australia.

A secondary data analysis revealed that there might be a correlation between the CAG repeat number and the efficacy of Miraxion™. The group of patients with a CAG repeat length of less than 45 in the "intent to treat" group that received Miraxion™ showed a statistically significant improvement over those patients that received placebo medication.

In the patient group with CAG repeats of less than 45 who adhered to the clinical trial protocol for Miraxion™, there was a 22.7% improvement in the Total Motor Score-4 (TMS-4) versus those patients receiving the placebo who demonstrated a 5.7% decline at the end of the 12 month study.

This improvement was observed over a six month period and was further maintained for an additional six months. In the following 12-month open label phase, all patients who had participated in the clinical trial were offered a "compassionate" supply. More than 3 years after the start of the clinical trial, 101 of the 135 patients enrolled in the study continued to be supplied with Miraxion™.

Amarin Corporation plc is currently in the planning stages for a second Phase Three clinical trial of Miraxion™ and will utilize this CAG repeat information to target patients who fit within the profile particularly relating to age of onset. According to Rick Stewart, Chief Officer of Amarin, "Improvement and stability are particularly beneficial if initiated at an early stage in this devastating disease. This could significantly extend a patient's professional activities, maintain a good quality of life and potentially defer the onset of the later stages of the disease."

The second Phase Three clinical trial will involve 400 HD patients in early 2005. Miraxion™ has been granted "fast track" designation by the FDA and has received Orphan Drug status in both the US and Europe. Miraxion™is also in clinical development for depression.

HDSA will continue to keep you apprised of developments related to the next Phase Three clinical trial for Miraxion™.

January 13, 2004 — HDSA Bulletin: Virus Delivers CNTF to HD Mice

The results of a mouse study examining the use of lentiviral vectors as a possible mode of delivery for CTNF were published in the January issue of Experimental Neurology, sending encouraging word of the potential for gene therapy in the treatment of Huntington's Disease (HD). Coalition for the Cure investigator Dr. Michael Hayden worked alongside researchers at the Swiss Federal Institute of Technology, the University of Coimbra in Portugal, and Emory University School of Medicine to conduct this study. The aim of this international group, funded in part by the Huntington's Disease Society of America (HDSA), was to determine the success of using a lentiviral vector for the long-term expression of ciliary neurotrophic factor (CNTF). CNTF has demonstrated neuroprotective effects and has reduced behavior deficits and brain degeneration in some HD mouse models. As a result, investigators are looking at gene therapy as a method to increase the amount of CNTF in brain cells of those with HD. Lentiviral vectors loaded with the gene for CNTF were injected into HD and wild-type mice when they were 4 months old. Not only could CNTF expression could still be seen up to a year after injection, but a decrease in motor activity connected with disease was observed in HD mice. These results are encouraging in regards to both gene therapy and the possible beneficial effects of CNTF in HD treatment. Dr. Hayden shared his thoughts on the significance of this study. 'This manuscript provides a proof of a principle for efficient delivery and expression of a gene to the striates and offers promise for gene therapy approaches for treatment of Huntington’s Disease.' Huntington's Disease Society of America

December 9, 2003 — HDSA Bulletin: Mixed Results Returned from Rizuzole Study

In the December 2003 issue of Neurology, the Huntington Study Group published the results of a trial conducted in partnership with the Huntington's Disease Society of America on a compound called riluzole. Principal investigators Drs. Frederick J. Marshall and Merit Cudkowicz with Senior Coalition Investigator Michael Hayden, Karl Kieburtz, Hongwei Zhao, John Penney, and Ira Shoulson concluded that the malignant side-effects of riluzole outweigh its limited antichorea abilities. Riluzole is a compound that diminishes the glutamatergic signals sent between brain cells. Since glutamate excitotoxicity is believed to contribute to HD pathogenesis, it seemed strong candidate for therapeutic treatment of HD. Early studies demonstrated that HD patients tolerated riluzole well and some decreases in chorea were seen. These factors prompted the HSG and HDSA to conduct an 8-week dose-ranging placebo-controlled study to evaluate the potential therapeutic benefits of the compound for HD patients. Investigators administered riluzole or a placebo at 100 mg/day or 200 mg/day in 63 HD patients in various locations around the country (including four HDSA Centers of Excellence). Treatment with the compound did reduce chorea and improved the UHDRS total motor score, though it did not improve functional capacity or other symptoms of HD. These gains were offset by elevations in ALT levels, which imply impairment of liver function. Based on these results, Dr. Marshall concluded, "The high cost of the medication, the need for ongoing monitoring of liver function, and the lack of benefit on other features of the illness prevent us from recommending the drug for routine use." However, Dr. Marshall continued to share, "A larger, longer-term study of riluzole in Huntington''s disease is currently underway in Europe, and may shed light on whether the drug has the ability to slow the progression of the underlying disease." Huntington's Disease Society of America

October 30, 2002 — HDSA Bulletin: Amarin Corporation describes preliminary results of LAX 101 in HD as "encouraging"

Amarin Corporation announced Monday, October 28, that preliminary results of a Phase 3 clinical trial of LAX 101, a novel and proprietary product being developed for treating HD, were promising.

Investigators used change in the Total Motor Score 4 (TMS 4) of the Unified HD Rating Scale over 1 year of treatment as the primary measure in the trial. They found that the subset of entrants complying with the trial protocol who could be evaluated for the full year showed a statistically significant difference between the LAX 101 and placebo groups with one of the analytical methods used. The result was not significant when those who dropped out or did not comply with the treatment protocol were included. These results were consistent with findings of a Phase 2 clinical trial that were reported by Amarin in January 2002.

LAX-101 was found to be well tolerated by patients throughout the trial. The results are from a multi-center, double-blind, randomized placebo-controlled study of LAX-101 which enrolled 135 HD patients at six sites located in the US, Canada, the UK and Australia.

Rick Stewart, chief executive officer of Amarin, stated "We are encouraged by the results of this trial and look forward to working closely with our partner, Laxdale Ltd., who is in discussions with the US Food and Drug Administration in relation to the findings."

LAX-101 has been granted a Fast Track designation by the FDA as well as having received Orphan Drug status in the US and Europe. Huntington's Disease Society of America