Synageva BioPharma Presents New Data From Phase 3 Study Of Sebelipase Alfa In Children And Adults With LAL Deficiency At The AASLD Meeting

LEXINGTON, Mass., Nov. 10, 2014 /PRNewswire/ -- Synageva BioPharma Corp. (NASDAQ: GEVA), a biopharmaceutical company developing therapeutic products for rare disorders, today announced that data from its Phase 3, global, double-blind, placebo-controlled trial evaluating sebelipase alfa in children and adults with lysosomal acid lipase deficiency (LAL Deficiency) were presented for the first time at a medical conference during the late-breaking session of The Liver Meeting®, the 65^th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

Positive top-line results from this trial were announced on June 30, 2014 and were a key focus of today's presentation.  The new data presented today at the AASLD meeting by a principal investigator described the magnitude of the impact of sebelipase alfa on a broad range of important disease-related abnormalities, and provided new insights into the severity of patients' liver disease and dyslipidemia at baseline. The investigator also presented data demonstrating sustained reductions in alanine aminotransferase (ALT, the study's primary endpoint and a marker of liver injury) and further improvements in LDL cholesterol at week 36 from the ongoing open-label extension period of the study.

"LAL Deficiency causes progressive and multisystemic organ damage including hepatic cirrhosis and accelerated atherosclerosis that can lead to sudden and unpredictable clinical complications," said Manisha Balwani, M.D., M.S., Assistant Professor of Genetics and Genomic Sciences and Assistant Professor of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, and principal investigator in the study. "The results from this Phase 3 trial demonstrated that sebelipase alfa, relative to placebo, improved key parameters associated with LAL Deficiency including markers of liver injury, dyslipidemia, and liver fat content.  Importantly, sustained reductions in markers of liver injury and further improvements in LDL cholesterol were observed with sebelipase alfa during the early part of the open-label extension period."

Trial design and baseline characteristics.  The Phase 3 trial enrolled 66 children and adults with LAL Deficiency.  Patients enrolled in the trial were randomized on a one-to-one basis to every other week infusions of sebelipase alfa (1 mg/kg) or placebo for the double-blind treatment period of 20 weeks.  LAL Deficiency patients enrolled in the trial presented with multiple clinically important abnormalities at baseline.  The median age of patients enrolled in the trial was 13 years of age (range 4-58) and fibrosis and/or cirrhosis was documented in 100% (32/32) of patients who had baseline biopsies.  Data from the oral presentation further revealed that of the patients who had biopsies at baseline, 47% (15/32) had bridging fibrosis (defined as Ishak score 3 or 4) and an additional 31% (10/32) of patients had cirrhosis.

Dyslipidemia was also common at baseline, with median LDL cholesterol levels of 204 mg/dL, which is in the very high category (greater than 190 mg/dL), and abnormally low median HDL cholesterol levels of 32.5 mg/dL, despite 39% (26/66) of patients already receiving lipid-lowering medications.  Data from today's presentation also showed that 58% (38/66) of patients had LDL cholesterol levels at baseline in the very high category (greater than 190 mg/dL) despite 24% (9/38) of these patients receiving lipid-lowering medications.

Impact on disease-related abnormalities.  The trial met the primary endpoint with 31% (11/36) of sebelipase alfa patients reaching normalization of ALT (defined as 34-43 U/L, depending on age and gender) compared with 7% (2/30) of placebo patients (p=0.027).  All sebelipase alfa patients showed a decrease in ALT with mean changes in ALT of -57.9 U/L and -6.7 U/L in the sebelipase alfa and placebo arms, respectively.  In addition, treatment with sebelipase alfa showed significant improvements in multiple disease-related parameters of dyslipidemia and liver injury (Table 1).

Table 1: Phase 3 trial efficacy at 20 weeks

^a Primary endpoint
^b Cannot be interpreted as significant due to the lack of statistical significance from the prior test under the pre-specified fixed sequence testing methodology

Safety overview.  The sebelipase alfa and placebo arms had a similar number of patients with reported adverse events.  Most adverse events during the double-blind treatment period were mild and unrelated to sebelipase alfa.  The adverse events occurring in three or more sebelipase alfa treated patients, and which occurred more commonly in treated than placebo patients, were headache (28% versus 20%), pyrexia or increased body temperature (25% versus 23%), oropharyngeal pain (17% versus 3%), nasopharyngitis (11% versus 10%), abdominal pain (8% versus 3%), constipation (8% versus 3%), nausea (8% versus 7%) and asthenia (8% versus 3%).  Serious adverse events were reported in two sebelipase alfa-treated patients and one placebo patient.  One patient experienced a serious adverse event described as an atypical infusion related reaction following treatment with sebelipase alfa and discontinued from the double-blind portion of the clinical trial.  The other sebelipase-alfa treated patient experienced gastritis, which was moderate in severity and unrelated to sebelipase alfa.

Two patients in the sebelipase alfa arm and four patients in the placebo arm experienced infusion-associated reactions during the double-blind portion of the study.  Six percent (2/35) of sebelipase alfa treated patients were anti-drug antibody positive at more than one time point during the double-blind treatment period with no apparent effect on safety or efficacy measures and no patients developed neutralizing antibodies during the double-blind period (Table 2).

Table 2: Phase 3 trial safety at 20 weeks

Preliminary results from open-label extension period.  Sixty-five of the 66 patients enrolled in the study have entered into a long-term, open-label extension period of the study.  Preliminary data presented at the meeting demonstrated that placebo patients from the double-blind 20-week period of the study who entered the extension period of the study experienced a similar response to sebelipase alfa as those patients initially treated during the double-blind 20-week period, namely, reductions in ALT and LDL cholesterol.  In addition, patients from the sebelipase alfa treatment arm of the double-blind 20-week period who entered the extension period of the study experienced sustained reductions in ALT and further reductions in LDL cholesterol at week 36.  The safety profile in the open-label period was consistent with that observed during the double-blind period.  One serious adverse event was observed (gastroenteritis) in the open-label period, which was unrelated to sebelipase alfa.

Sebelipase Alfa for LAL Deficiency

LAL Deficiency is a serious, underdiagnosed disease that manifests with significant morbidity and early mortality and can lead to sudden and unpredictable clinical complications.  LAL Deficiency often manifests in childhood but can be diagnosed at all ages with a simple blood test.  LAL Deficiency is caused by genetic mutations that result in decreased LAL enzyme activity in the lysosomes across multiple body tissues, leading to the buildup of fatty material in the liver, blood vessel walls and other tissues.

Sebelipase alfa is a recombinant form of the human LAL enzyme being developed by Synageva as an enzyme replacement therapy for LAL Deficiency.  Sebelipase alfa has been granted orphan designation by the FDA, the EMA, and the Japanese Ministry of Health, Labour and Welfare.  Additionally, sebelipase alfa received fast track designation by the FDA, and Breakthrough Therapy designation by the FDA for LAL Deficiency presenting in infants. 

Synageva routinely posts information that may be important to investors in the "Investor Relations" section of the company's website at www.synageva.com.  Synageva encourages investors and potential investors to consult this website regularly for important information about the company.

Further information regarding Synageva is available at www.synageva.com.

Medical information regarding sebelipase alfa and LAL Deficiency is available by email at [email protected].

Forward-Looking Statements

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SOURCE Synageva BioPharma Corp.

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