Despite previous data showing efficacy of Miraxion in a subset of Huntington's disease patients, Amarin Corp. plc's drug failed to hit primary and secondary endpoints in two Phase III studies.

The news sent investors fleeing the London-based firm's stock all day, with the trading volume more than 100 times its average. Shares (NASDAQ:AMRN) dropped 78.1 percent, or $2.95, Tuesday to close at 83 cents.

Top-line results from the 600-patient Phase III program found no statistically significant difference between Miraxion and placebo in either the primary endpoints, as defined by a change in the Total Motor Score 4 (TMS-4) component of the Unified Huntington's Disease Rating Scale, or secondary endpoints, which included cognition and Total Function Capacity outcomes. The onset and progression of Huntington's is believed to be linked to a genetic mutation, and analyses from a failed Phase III study of Miraxion, reported in 2004, indicated a correlation between CAG repeat number and change in TMS-4 score, suggesting that the drug would be efficacious in patients with a CAG score of 44 or lower. However, results for that patient population, which made up about 70 percent of the overall study program, were similar to results for the entire trial population.

Those data were of "great disappointment to all of us," said Amarin CEO Rick Stewart, who, along with the rest of the management team, learned of the top-line results Monday evening. Full study data have not yet been disclosed.

"We do not fully understand why we were not able to replicate" the data seen in the earlier studies, he told investors during a conference call.

Amarin's pivotal program was designed as double-blind, placebo-controlled studies to compare 1 gram of Miraxion, administered twice daily, to placebo. The first study, TREND-HD, enrolled 316 patients in the U.S. and Canada, and the second study, TREND-EU, involved 290 patients across Europe.

Miraxion, a semi-synthetic, highly purified derivative of (all-cis) 5,8,11,14,17-eicosapentaenoic acid designed to stabilize cell membranes and the mitochondrial integrity of neurons, is one of the few Huntington's disease drugs in late-stage development. Palo Alto, Calif.-based Avicena Group Inc. anticipates starting a Phase III program late this year or in 2008 to evaluate HD-02, a formulation of creatine, and San Francisco-based Medivation Inc. began a Phase I/II trial of Dimebon, an oral, small molecule, in October. A number of other companies have Huntington's programs earlier in their development pipelines.

The biggest disappointment is for the Huntington disease patients and their families, Stewart said, who will have to wait longer for an effective therapy. Existing treatments are limited to managing the symptoms of Huntington's, a genetic disorder that results in the degeneration of neurons in the areas of the brain controlling movement, emotion and cognition.

He added that Amarin remains "committed to neurology research," though Miraxion's future is less certain. The drug, which Amarin first licensed from the privately held Scottish firm Laxdale Ltd. in 2000 before buying out Laxdale four years later, also is in development for Parkinson's disease and depressive disorders. Stewart said it would be "premature" to comment on further development plans in those indications before further Phase III analysis is completed.

"Clearly, Miraxion is our main driver," Stewart said, "but we've been building our CNS pipeline over the past year." He assured investors that the company's existing cash - $29 million, as of March 30 - would be sufficient to advance those programs initially.

Most of its additional programs involve efforts to improve existing compounds, which offered a way to "de-risk" Miraxion development, Stewart said. Those other programs include an oral formulation of apomorphine, a product approved for treating the "off" symptoms in advanced Parkinson's disease patients, and a nasal version of lorazepam for treating emergency seizures in epilepsy patients.

Amarin also has a combinatorial lipid program, which combines lipids with existing drugs for central nervous system disorders to improve transport across the blood-brain barrier and provide greater efficacy. The first two candidates from that program have entered preclinical development.

Beyond that, the company will continue to enhance its pipeline through "in-licensing, partnering and the acquisition of marketed products," Stewart said.

Amarin has not yet reported its first-quarter results. For the three months ending Dec. 31, the company reported a net loss of $6.5 million, or 7 cents per share.