Amarin Corp. plc's plans for Phase III trials with a Huntington's disease product, Miraxion, have been aided by further analysis of data from a prior Phase III study.
After analyzing gene variant data from the earlier trial, which failed to show a statistically significant benefit in its primary endpoint, the London-based company identified a group of participants for whom Miraxion did benefit. The study's primary endpoint was a measure of the change over a one-year period in the Total Motor Score-4 (TMS-4) score of the Unified Huntington's disease rating scale.
Alan Cooke, Amarin's chief financial officer, told BioWorld Today: "We've had discussions with the FDA on the protocol, and got some feedback from EMEA on the protocol, and that, along with the various data we got from the [prior] Phase III trial, is very useful in helping us design the [upcoming] trials."
The company found that a subset of patients with Huntington's disease, which is believed to be caused by a genetic mutation of the cytosine, adenosine and guanine (CAG) polymorphic trinucleotide repeat, exhibited a correlation between the CAG repeat number and the change in their TMS-4 score. There also is believed to be a direct link between CAG repeat length and age of onset, disease progression and clinical symptoms. CAG repeat length can be measured by way of a genetic blood test.
Cooke said it is still too early to say whether the upcoming Phase III trials would target the patient subset alone or continue to test Miraxion in a broader disease population. But he added that such a protocol would be finalized in the next couple of weeks.
The studies, which Amarin plans to begin early next year, will include more than 400 Huntington's disease patients. Their primary endpoint likely would mirror the original Phase III trial, and they likely would last about six months after completing recruitment.
But for Amarin to begin the studies, it first must complete its proposed acquisition of Laxdale Ltd. in a transaction that is subject to Amarin shareholder approval. Amarin signed a definitive agreement last month to acquire Laxdale, and probably will hold a special shareholder meeting next month.
The companies' relationship dates to November 2000, when Amarin gained a license to U.S. rights for Miraxion in Huntington's disease from privately held Laxdale.
"The acquisition of Laxdale, of course, would bring us full economic [benefits] in the U.S. market," Cooke said. "In the current circumstances under the license agreement, Laxdale is fully responsible for Phase III and getting it approved through the FDA and European authorities at its full cost. For that reason, because they're taking the development risk, they had a significant share in the revenues and profits of the U.S. market," but the acquisition would limit royalty obligations back to Laxdale.
Stirling, Scotland-based Laxdale already filed for European approval of the product, which formerly was labeled LAX-101, based on its first Phase III study of Miraxion. To explore a possible relationship between Miraxion's efficacy and the number of CAG repeats, the company conducted an exploratory analysis after completing the trial and found a correlation between the CAG repeat number and the change in TMS-4 score in Miraxion patients.
To explore that effect further, patients were split into two groups based on the median number of CAG repeats. Those patients that took Miraxion and had a CAG repeat length of less than 45 comprised the responsive group, and the effect was consistent at all six trial centers in the U.S., Canada, the UK and Australia. In total, 67 of the 135 patients in the initial Phase III study had the specific gene variant. It is estimated that patients with a CAG repeat length of less than 45 represent more than 65 percent of all Huntington's disease patients.
Those 67 patients with a CAG repeat length of less than 45 showed a statistically significant improvement over patients receiving placebo (p=0.029). Also, 44 patients with a CAG repeat length of less than 45, who observed the clinical trial protocol receiving Miraxion, showed a 22.7 percent improvement in TMS-4 score vs. those receiving placebo, who showed a 5.7 percent deterioration at the end of the 12-month study (p=0.006). The improvement was observed over a six-month period and maintained for another six months. The improvement also was maintained in the 12-month, open-label continuation phase of the trial.
Miraxion is a fast-track product for Huntington's disease in the U.S., and has orphan drug status in the U.S. and Europe. It also is in Phase IIa development for depression.
Cooke said Amarin plans to partner Miraxion for depression in an agreement that also likely would cover marketing in the U.S. and abroad.
The company's clinical pipeline behind Miraxion is empty until the Laxdale acquisition closes, Cooke said, adding that the transaction would include additional candidates for a variety of neurological indications. Amarin also is looking to close an equity financing before beginning Miraxion's continued Phase III development.