Clinical Trials

Date: 2016-11-11

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at The Liver Meeting 2016, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), in Boston

Company: Synageva BioPharma (USA - MA), now Alexion Pharmaceuticals (USA - CT)

Product: sebelipase alfa

Action mechanism:

enzyme replacement therapy. Sebelipase alfa (SBC-102) is a recombinant form of the human lysosomal acid lipase (LAL) enzyme under development by Synageva as an enzyme replacement therapy for lysosomal acid lipase deficiency (LAL Deficiency). LAL Deficiency is a rare autosomal recessive lysosomal storage disease (LSD) caused by a marked decrease in LAL enzyme activity that results in the buildup of fatty material in the liver, blood vessel walls, and other tissues and organs. 
Kanuma™ (sebelipase alfa) is approved in the European Union for the treatment of patients of all ages with LAL-D. The FDA granted Breakthrough Therapy designation for Kanuma for LAL Deficiency presenting in infants and accepted the Kanuma BLA for Priority Review. In addition, a New Drug Application for Kanuma has been submitted to Japan's Ministry of Health, Labour and Welfare

Disease: lysosomal acid lipase deficiency (LAL Deficiency) 

Therapeutic area: Rare diseases

Country:

Trial details:

The multicenter, randomized, placebo-controlled ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) study of children and adults with LAL-D included a 20-week double-blind treatment period and an ongoing open-label period. Sixty-six patients (ages 4-58 years) were enrolled in the study (36 received Kanuma and 30 received placebo) and 65 patients entered the open-label period. Most patients (47/66) were under 18 years of age. All 66 patients had an elevated ALT at baseline (?1.5 times the upper limit of normal). The primary efficacy endpoint was normalization of ALT levels. Additional efficacy endpoints included evaluations of other biochemical markers of liver function, serum lipid levels, hepatic fat content, organ volume, and liver histopathology in a subset of patients. Baseline assessments demonstrated significant disease burden in the patient population studied.

Latest news:

* On November 11, 2016, Alexion Pharmaceuticals announced that researchers presented new longer-term data from an ongoing, open-label extension of the pivotal Phase 3 ARISE trial of Kanuma® (sebelipase alfa) in children and adults with lysosomal acid lipase deficiency (LAL-D). Two-thirds of patients (8/12) treated with Kanuma® for 52 weeks had a reduction in liver fibrosis stage from baseline, as measured by Ishak score. Moreover, half of patients (6/12) achieved at least a 2-stage reduction, including five patients who had fibrosis at baseline and one who had cirrhosis at baseline. Reduction of liver fibrosis stage was accompanied by sustained improvements in alanine aminotransferase (ALT), LDL cholesterol (LDL-C), and liver fat content through 52 weeks of Kanuma® treatment. These data were reported in a poster presentation at The Liver Meeting 2016, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), in Boston .
Researchers at AASLD also presented new long-term data from the ARISE study showing rapid and sustained improvements in important markers of liver injury and lipid abnormalities in children and adults with LAL-D treated with Kanuma®. With 76 weeks of Kanuma® treatment, nearly all patients (98 percent) had a sustained reduction in ALT levels, with a mean reduction from baseline of 56 percent.
Researchers presented data from the ongoing, open-label period of the Phase 3 ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) trial of Kanuma in children and adults with LAL-D that evaluated the effect of long-term Kanuma treatment on liver fibrosis stage. This poster was selected as a Presidential Poster of Distinction at AASLD. Following the 20-week, double-blind, randomized, placebo-controlled period of the study, 65 patients began the open-label phase and were treated with Kanuma for up to 130 weeks, including 35 patients who were treated with Kanuma during the double-blind period and 30 who were treated with placebo during the double-blind period. Paired liver biopsies were taken in 20 patients (ages 5 to 59 years) at baseline and study Week 52, including 12 patients who initially received Kanuma in the double-blind period and 8 patients who initially received placebo in the double-blind period. The 7-point Ishak staging system was used to assess fibrosis and cirrhosis.
Of the 12 patients who were biopsied at baseline and 52 weeks of Kanuma treatment, six achieved a ?2-stage reduction in liver fibrosis from baseline, and two achieved a 1-stage reduction. Three patients showed no change in fibrosis stage and one patient had an increase. Of the six patients who had a 2-stage reduction from baseline to week 52, one had cirrhosis and five had stage 3 fibrosis at baseline. In addition to achieving a 2-stage reduction in liver fibrosis, this group of patients demonstrated mean reductions of 61 percent in ALT, 40 percent in LDL-C, and 32 percent in liver fat content after 52 weeks of treatment. Among the 8 patients who were biopsied at baseline and at study week 52 (reflecting 30 weeks of Kanuma treatment), four had a 1-stage reduction in fibrosis, three had no change, and one had an increase.
Additionally, among patients with paired biopsy data at baseline and week 20, a significantly higher proportion of patients in the Kanuma arm had improvement or no change from baseline in hepatic steatosis compared with patients in the placebo arm (94 percent vs. 50 percent; p = 0.0184). Among the 12-patient biopsy cohort that received Kanuma for 52 weeks, median percentage of steatosis decreased by 37 percent from baseline.
Most adverse events during the open-label extension period were mild to moderate in intensity. The most common treatment-emergent adverse events were nasopharyngitis, headache, pyrexia, and cough. No patient discontinued the open-label study because of adverse events. Thirteen patients (20 percent) experienced an infusion-associated reaction during the open-label period. One patient had a serious reaction that was considered treatment-related; the patient stopped taking Kanuma but later resumed therapy.
Long-Term Benefit of Sebelipase Alfa over 76 Weeks in Children and Adults with Lysosomal Acid Lipase Deficiency (ARISE Trial): Researchers at AASLD also presented new 76-week results from the open-label extension of the ARISE trial in patients with LAL-D. Fifty-two week findings were previously reported at the 5th World Congress of Pediatric Gastroenterology , Hepatology and Nutrition (WCPGHAN) in October 2016 , demonstrating that nearly all patients (97 percent) who were treated with Kanuma for 52 weeks had a rapid and sustained reduction in ALT, with 47 percent achieving ALT normalization.
New data presented at AASLD showed that after 76 weeks of Kanuma treatment, 98 percent (60/61) of patients had a sustained reduction in ALT from baseline, 51 percent (31/61) achieved ALT normalization, and 65 percent (37/57) achieved aspartate aminotransferase (AST) normalization. Marked and sustained improvements in ALT and AST occurred when patients who had initially received placebo during the double-blind period switched to Kanuma, mirroring those improvements observed in patients receiving Kanuma from the start of the double-blind period. Patients also had improvements in lipid abnormalities, including decreases in mean LDL-C, non-HDL cholesterol, and triglycerides, and increases in mean HDL cholesterol.
The safety profile of Kanuma during the extended open-label period, as described above, was consistent with that observed in the double-blind period.

* On October 6, 2016, Alexion Pharmaceuticals announced that researchers presented new long-term data from an ongoing, open-label extension of the pivotal Phase 3 ARISE trial of Kanuma® (sebelipase alfa) in children and adults with lysosomal acid lipase deficiency (LAL-D). At 52 weeks of Kanuma treatment, nearly all patients (97 percent) who had received Kanuma® from the start of the double-blind period had a rapid and sustained reduction in alanine aminotransferase (ALT), with a mean percent reduction of 53 percent, and an increase from 31 percent (11/36) to 45 percent of patients (15/33) achieving ALT normalization. Similarly, after 52 weeks of Kanuma treatment, nearly all patients (97 percent) who had initially received placebo during the double-blind period had a reduction in ALT, with a mean percent reduction of 52 percent, and 48 percent of patients (14/29) achieving ALT normalization.1 Sustained improvements were also observed in both groups in markers of lipid abnormalities (including LDL cholesterol, non-HDL cholesterol, triglycerides, and HDL cholesterol) through 52 weeks of Kanuma treatment. These data were reported in a poster presentation at the 5th World Congress of Pediatric Gastroenterology , Hepatology and Nutrition (WCPGHAN) in Montréal, Canada .
Long-term Benefit of Sebelipase Alfa Over 52 Weeks in Children and Adults With Lysosomal Acid Lipase Deficiency (ARISE Trial): In a poster session, 52-week data were presented from the ongoing, open-label period of the Phase 3 ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) trial of Kanuma in children and adults with LAL-D. Findings from the 20-week, double-blind, randomized, placebo-controlled period of the study (N=66) were published in the New England Journal of Medicine in September 2015 , and showed that Kanuma was associated with a significantly greater proportion of patients achieving ALT normalization compared with placebo (31 percent vs. 7 percent, p=0.03).5 Normalization was defined in the trial as ALT below the age- and gender-specific upper limit of normal provided by the central laboratory performing the assay. One hundred percent of Kanuma-treated patients had a reduction in ALT at 20 weeks with a mean percent reduction of 53 percent. This compares with 63 percent of placebo patients who had a reduction in ALT at 20 weeks, with a mean percent reduction of 6 percent. At 20 weeks, patients treated with Kanuma also showed significant improvement versus placebo in six secondary endpoints, including change in LDL cholesterol, change in non-HDL cholesterol, AST normalization, change in triglycerides, change in HDL cholesterol, and change in hepatic fat content.
Sixty-five patients began the open-label portion of the study (ages 4-58 years; median age of 13 years) and were treated with Kanuma for up to 130 weeks, including 35 patients previously treated with Kanuma and 30 previously treated with placebo during the double-blind period. For both groups, efficacy assessments were measured at 52 weeks of Kanuma exposure, except for liver fat content and liver volume, which were measured at a fixed time-point of 52 weeks, reflecting 30 weeks of Kanuma exposure for patients initially treated with placebo and 52 weeks of Kanuma exposure for patients initially treated with Kanuma.
After 52 weeks of Kanuma exposure, 47 percent (29/62) of patients achieved ALT normalization and 56 percent (33/59) of patients achieved aspartate aminotransferase (AST) normalization. Patients also had improvements in lipid abnormalities, including mean LDL cholesterol, non-HDL cholesterol, triglycerides, and HDL cholesterol. Across all measures, results after 52 weeks of treatment with Kanuma were similar for patients previously treated with Kanuma during the double-blind period and patients treated with placebo during the double-blind period. In addition, at a fixed time-point of 52 weeks, hepatic fat content was reduced by a mean of 21.9 percent for patients initially treated with Kanuma and by 28.1 percent for patients initially treated with placebo. Liver volume was reduced by a mean of 13.5 percent for patients initially treated with Kanuma and by 11.4 percent for patients initially treated with placebo.
The safety profile of Kanuma during the extended open-label period was consistent with that observed in the double-blind period. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, and no patient discontinued the open-label study because of adverse events. The most common TEAEs in the open-label period were headache (40 percent), nasopharyngitis (35 percent), and cough (28 percent). Twelve patients (18 percent) experienced an infusion-associated reaction during the open-label period; all but one reaction were mild or moderate in intensity.
Additional Data Presented at WCPGHAN: Researchers are also presenting updated results from the ongoing, open-label, Phase 2/3 VITAL study of Kanuma in infant patients who presented with evidence of growth failure or rapidly progressive LAL-D within the first 6 months of life. Findings were previously reported at the 12th Annual WORLDSymposium™ in March 2016 , demonstrating that as of January 2016 , 5 of 9 patients (56 percent) treated with Kanuma had survived beyond two years of age. New data being presented at WCPGHAN show that as of August 2016 , 5 of 9 Kanuma-treated infants had survived beyond three years of age, with the oldest patient now more than five years old. All five patients continue to receive treatment.6
Alexion will also present information on the first global LAL-D registry, which aims to improve patient outcomes through a better understanding of the treatment and care of this ultra-rare disease. The registry collects long-term, real-world data on the epidemiology of LAL-D, as well as patient outcomes data.

* On March 3, 2016,  Alexion Pharmaceuticals announced that researchers presented new two-year data from an ongoing, open-label Phase 2/3 trial of Kanuma™ (sebelipase alfa) in infants with lysosomal acid lipase deficiency. Data from this study demonstrated a substantial survival benefit (56 percent, or 5 out of 9) to beyond 2 years of age for patients with rapidly progressive LAL-D during infancy who were treated with Kanuma, with the longest-treated patient surviving to over 5 years of age. Patients also had improvements in a number of key parameters, including weight gain, important markers of liver disease, gastrointestinal symptoms, anemia, and hepatosplenomegaly (enlargement of both the liver and spleen), and 4 out of 5 patients demonstrated normal development. These data were reported in an oral presentation at the 12th Annual WORLDSymposium™ in San Diego . Additionally, researchers reported favorable findings from an analysis of safety data from three ongoing, long-term trials evaluating Kanuma in children and adults with LAL-D.

* On September 9, 2015, Alexion Pharmaceuticals announced that data from the pivotal Phase 3 ARISE study evaluating the safety and efficacy of Kanuma™ (sebelipase alfa) in children and adults with lysosomal acid lipase deficiency (LAL-D) have been published in the September 10 issue of the New England Journal of Medicine (NEJM). In the study, Kanuma™ met the primary endpoint of alanine aminotransferase (ALT) normalization compared with placebo (31% vs. 7%, p=0.03) as well as six secondary endpoints
In addition to the NEJM publication, the Journal of Pediatric Gastroenterology & Nutrition recently published the largest longitudinal review of children and adults with LAL-D. In this observational study, ALT was elevated in more than 90% of patients, LDL cholesterol was abnormal in nearly 65% of patients (mean value of 202.9 mg/dl), HDL cholesterol was abnormal in more than 40% of patients, and the overall frequency of liver transplantation was 13%. Reductions in LDL were typically small in patients taking lipid-lowering medication. Findings from this study confirm the significant burden of LAL-D despite historical supportive care.
 * On November 10, 2014, Synageva BioPharma 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 at a medical conference during the late-breaking session of The Liver Meeting®, the 65th 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 (see below) and were a key focus of this presentation. The new data presented 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 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 the 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

 

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

Event type	Sebelipase alfa (n=36) # patients (%)	Placebo (n=30) # patients (%)
Adverse Events (AEs)	31 (86%)	28 (93%)
Serious Adverse Events (SAEs)	2 (5.6%)	1 (3.3%)
Infusion-Associated Reactions (IARs)	2 (6%)	4 (13%)

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.

* On October 23, 2014, Synageva BioPharma announced two poster presentations of sebelipase alfa data for LAL Deficiency and a satellite symposium at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) annual meeting being held October 23-26, 2014 in Atlanta, GA. Reduced steatosis and fibrosis observed with sebelipase alfa from an ongoing Phase 1/2 extension study in adults with LAL Deficiency. Nine adults with LAL Deficiency enrolled in the Phase 1/2 trial with sebelipase alfa. After completing the initial four-week portion of the trial, patients were allowed to continue treatment with sebelipase alfa as part of a long-term, open-label extension study. Eight of nine patients enrolled in the extension study and continue treatment with sebelipase alfa. The ninth patient delayed entering the extension study and, after 10 months without treatment, experienced progression of liver disease requiring an urgent liver transplant.

As previously reported, with six of the eight patients enrolled in the ongoing Phase 1/2 extension study completing two years of treatment, sebelipase alfa continued to demonstrate sustained reductions in the biomarkers of liver damage (both ALT and AST), frequently into the normal range, from the pre-treatment baseline to two years of the extension study. Sebelipase alfa also maintained improvements in dyslipidemia associated with LAL Deficiency, with decreases in LDL and triglycerides and increases in HDL from the pre-treatment baseline to two years of the extension study. 

Most adverse events through the two years of the extension study were mild and unrelated to sebelipase alfa. Infusion associated reactions were uncommon, generally mild and gastrointestinal in nature (diarrhea, abdominal cramping). Two serious adverse events (cholecystitis/cholelithiasis) considered unlikely related to sebelipase alfa occurred in one patient and this patient continues treatment with sebelipase alfa in the study.

Updated data from this ongoing Phase 1/2 trial presented at the NASPGHAN meeting include pre-treatment and post-sebelipase alfa treatment liver biopsies obtained from two patients. Compared to historical pre-treatment biopsies, biopsies obtained after more than 18 months of treatment with sebelipase alfa showed less steatosis and fibrosis based on assessments performed by local pathologists. One patient had a pre-treatment biopsy at 17 years of age with notable steatosis assessed visually and extensive fibrosis with numerous fibrous bridges and initial nodulations. A subsequent liver biopsy conducted one and a half years after treatment with sebelipase alfa at 22 years of age showed substantial decreases in steatosis with less fibrosis localized to periportal areas associated with some septa. A second patient had a pre-treatment liver biopsy at 37 years of age revealing significant steatosis and fibrosis. A subsequent liver biopsy conducted two years after treatment with sebelipase alfa at 44 years of age showed mild steatosis with no significant fibrosis.

Updated results from an ongoing Phase 2/3 trial with sebelipase alfa in infants with LAL Deficiency: The ongoing Phase 2/3 trial is an open-label, multicenter study of sebelipase alfa in infants with LAL Deficiency. Infants with growth failure before six months of age were eligible to enroll and receive weekly infusions with sebelipase alfa (1-3 mg/kg). The primary endpoint of the trial is survival at 12 months of age. In a natural history study, failure to thrive, liver complications and mortality were confirmed in infants with LAL Deficiency. The median age (range) for infants at symptom onset, diagnosis, and death was 1.0 month (0-6.0), 2.6 months (1.0-17.7), and 3.7 months (1.4-46.3), respectively. Growth failure and aggressive liver disease contributed to early mortality. Transaminase levels (ALT and/or AST), abnormal at diagnosis, markedly increased with disease progression. Hematopoietic stem cell transplants were performed in 10 infants; seven of these 10 infants died before nine months of age and three infants died between 26.9¬-¬46.3 months of age.

Data from the nine infants enrolled in the clinical trial were presented at the meeting. Patients with previous hematopoietic stem cell or liver transplant were excluded from this study. The median age of infants at first infusion with sebelipase alfa was 3.0 months. The median baseline liver function tests (ALT and AST of 145 IU/L and 125 IU/L, respectively) revealed underlying liver dysfunction and high baseline ferritin levels (median 586 ug/L) indicated macrophage activation. Diarrhea and vomiting, hepatomegaly, splenomegaly, and adrenal calcification were also common.Six infants met the primary endpoint of survival at 12 months of age and five infants continue on treatment with sebelipase alfa. In addition to improved survival relative to the historical cohort, all infants demonstrated improved weight gain, improvement of gastrointestinal symptoms, and reductions in hepatosplenomegaly. In addition to these clinical effects, rapid improvements in biochemical and hematological markers including ALT, AST, hemoglobin, and bilirubin were also observed. Four infants died during the study. Three infants died shortly after the start of the study, unrelated to sebelipase alfa, and one infant who met the primary endpoint of survival at 12 months of age subsequently died at 15 months of age, and this was considered unlikely related to treatment with sebelipase alfa. 

Adverse events with sebelipase alfa were mostly mild to moderate. Serious adverse events were mainly related to central line infections or hospitalizations for treatment with antibiotics. One patient experienced three related serious adverse events that included fever, malaise, and tachycardia developed during the infusion of sebelipase alfa. Four infants were previously described as having developed anti-drug antibodies and only one infant remains anti-drug antibody positive at the last data cut. All four infants continue on infusions with sebelipase alfa.

* On June 30, 2014, Synageva BioPharma announced that the global, randomized, double-blind, placebo-controlled Phase 3 ARISE trial of sebelipase alfa in 66 children and adults with lysosomal acid lipase deficiency (LAL Deficiency) met the primary endpoint of normalization of alanine aminotransferase (ALT), a marker of liver injury (p=0.027). In addition, sebelipase alfa significantly improved multiple other disease-related abnormalities as measured by a number of secondary endpoints. LAL Deficiency patients enrolled in the trial presented with multiple clinically important abnormalities at baseline. Fibrosis and/or cirrhosis was documented in 100% (32/32) of patients who had baseline biopsies even though the median age of patients enrolled in the trial was only 13 years. Dyslipidemia was common at baseline, with a median LDL cholesterol of 204 mg/dl (which is in the very high category of > 190 mg/dl), and an abnormally low median HDL cholesterol of 32.5 mg/dl. 

Impact on Dyslipidemia. In addition to demonstrating a statistically significant improvement in ALT normalization, sebelipase alfa improved dyslipidemia with statistically significant reductions in LDL cholesterol (p < 0.001), non-HDL cholesterol (p < 0.001) and triglycerides (p=0.038), as well as a statistically significant increase in HDL cholesterol (p < 0.001), all compared with placebo from baseline to the completion of the double-blind treatment period of 20 weeks.

Impact on Other Liver Abnormalities. Statistically significant improvements were also seen in AST normalization (p < 0.001) and in liver fat fraction as assessed by multi-echo gradient echo (MEGE) magnetic resonance imaging (MRI) (p < 0.001). Paired liver biopsies at baseline and at 20 weeks were available in 26/66 patients. Of these, 63% of patients treated with sebelipase alfa (10/16) had improvement in hepatic steatosis compared to 40% of patients on placebo (4/10). This difference did not reach statistical significance. Although the hierarchical fixed-sequence testing statistical methodology did not allow for a formal assessment of the remaining secondary endpoint, decreased liver volume as assessed by MRI was observed with sebelipase alfa compared with placebo.

Sebelipase Alfa 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 in nature 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 body temperature increased (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%). One patient discontinued from the double-blind portion of the clinical trial. This patient experienced a serious adverse event described as an atypical infusion related reaction following treatment with sebelipase alfa. Four patients in the placebo arm and two patients in the sebelipase alfa arm experienced infusion associated reactions during the double-blind portion of the study.

Synageva plans to complete submission of a Biologic License Application (BLA) to the FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for sebelipase alfa for the treatment of LAL Deficiency by the end of the first quarter of 2015.

Is general: Yes