Rare disease specialist Synageva Biopharma Corp. reported top-line phase III data showing that sebelipase alfa (SBC-102), its enzyme replacement therapy for lysosomal acid lipase (LAL) deficiency, met its primary endpoint and several secondary endpoints. The results, reported after-hours Monday, showcased the therapy's impact on multiple symptoms of LAL deficiency, positioning Synageva to file both FDA and EMA registration applications for the therapy by the end of the first quarter of 2015.

Despite normalizing levels of the liver injury marker alanine aminotransferase (p = 0.027), thus meeting the primary endpoint of the trial, the therapeutic did not demonstrate a statistically significant improvement on a biopsy-based measure of abnormal liver fat accumulation, or hepatic steatosis, sending shares (NASDAQ:GEVA) tumbling 13.7 percent, or $14.35, to close at $90.45 Tuesday.

That shortfall may have been due to the fact that paired liver biopsies were available only for 26 of the 66 patients who participated in the trial, Leerink Partners LLC analyst Joseph Schwartz suggested in a recent investor note.

Out of the 26 patients for which paired biopsies were available, 63 percent of those treated with sebelipase alfa showed improvement in hepatic steatosis compared to 40 percent of patients on placebo. The company attributed the shortfall of available paired samples to the fact that many study participants were children and difficult-to-control sampling variability. A separate magnetic resonance imaging-based assessment of liver volume did show statistically significant improvements (p < 0.001) provided by sebelipase alfa as compared with placebo, the company said.

The ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) trial enrolled 66 children and adults with LAL deficiency. Patients enrolled in the trial were randomized on a 1-to-1 basis to every-other-week infusions of sebelipase alfa (1 mg/kg) or placebo for the double-blind treatment period of 20 weeks. A combined phase II/III study in infants with rapidly progressive LAL deficiency showed six of the nine infants enrolled met the primary endpoint of survival to 12 months of age.

Patients receiving sebelipase alfa showed improvements on multiple secondary endpoints, including decrease in cholesterol, normalization of the liver enzyme AST, decrease in triglycerides, increase in HDL cholesterol, decrease in liver fat content, improvement in hepatic histology and decrease in liver volume. All 66 patients in the phase III study are now rolling over to active treatment.

The sebelipase alfa and placebo arms had similar numbers of adverse events, most of which were mild and unrelated to sebelipase alfa, the company said. The most common problems in treated patients were headache, body temperature increases, sore throat, inflammation of the nose and pharynx, abdominal pain, constipation, nausea and weakness. One patient dropped out of the double-blind portion of the trial after an "atypical infusion-related reaction" following treatment with sebelipase alfa. Four patients in the placebo arm and two patients in the sebelipase alfa arm had less serious reactions to the infusion.

Children and adults with LAL deficiency, also known as Wolman disease, suffer from chronic liver injury with liver fibrosis that can lead to cirrhosis. The defect in lipid metabolism leads to dyslipidemia and, often, elevated LDL cholesterol. While LAL enzymes take care of breaking down lipids in the lysosomes of healthy individuals, in patients with LAL deficiency, inherited mutations in both copies of the lipogene cause a significant decrease in LAL enzyme activity, leading to the abnormal build-up of fats in the cells in the liver, intestines and other tissues.

Synageva has orphan drug designations for sebelipase alfa from the FDA, EMA and the Japanese Ministry of Health, Labour and Welfare. In addition, the therapy received fast track designation by the FDA and, for infants with LAL deficiency, the agency's breakthrough therapy designation. (See BioWorld Today, March 7, 2014.)

"In our view, approval is now fairly de-risked," wrote Schwartz. Nonetheless, he voiced caution, suggesting that LAL deficiency patients may be hard to find. "Many LAL-D patients blend in with the general hyperlipidemia/liver disease population, and it is unclear how many require treatment with a potent (enzyme replacement therapy)," he wrote.

Citi Research analyst Christopher Mortko initiated coverage of Synageva Tuesday with a "neutral" rating and a $113 price target. Cautioned by concerns similar to Schwartz's regarding the ease with which patients will be identified, Mortko is modeling sebelipase alfa's peak sales of $700M. The remaineder of Synageva's pipeline of protein therapies for severe genetic disorders is too early in its development to value, Mortko wrote. The most advanced prospect, SBC-103, being developed for mucopolysaccharidosis IIIB, is set to enter clinical studies in mid-2014.

With sebelipase alfa testing complete, Synageva of Lexington, Mass., is well provisioned to carry its other pipeline programs ahead. The company reported cash reserves of $575 million as of April 30, just before pricing the largest underwritten public offering for a biotech so far in 2014, seeking to raise $211.5 million from a market hungry for rare disease winners. (See BioWorld Today, March 7, 2014.)