Alexion Pharma (ALXN) Announces New Long-Term Kanuma Phase 3 Data in LAL-D

October 6, 2016 4:31 PM EDT

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Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN) 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), a genetic and progressive ultra-rare metabolic disease. 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.

“LAL-D is a devastating and progressive disease that can lead to potentially life-threatening consequences, including cirrhosis and severe dyslipidemia,” said Martin Mackay, Ph.D., Executive Vice President and Global Head of R&D at Alexion. “Data from the open-label extension of the ARISE study show sustained improvements in several key disease markers and demonstrate that continued treatment with Kanuma for 52 weeks enabled a greater percentage of patients to achieve ALT normalization compared with the initial 20-week period. These long-term results reinforce the benefits of ongoing treatment with the first and only approved therapy for patients with LAL-D.”

LAL-D is a genetic, chronic and progressive ultra-rare metabolic disease associated with significant morbidity and premature mortality.2 Ultra-rare diseases are defined as diseases that affect fewer than 20 patients per 1 million of the general population.3 Patients with LAL-D can experience a rapid onset of life-threatening disease manifestations, and without treatment, the youngest patients typically face premature death within a matter of months. Unfortunately, children and adults with LAL-D are often undiagnosed or misdiagnosed, despite experiencing rapidly progressive organ damage that can lead to severe and life-threatening outcomes. LAL-D is caused by genetic mutations that result in a marked decrease or loss in vital LAL enzyme activity in the lysosomes across multiple body tissues, leading to the chronic build-up of cholesteryl esters and triglycerides in the liver, blood vessel walls, and other organs.2,4

Kanuma is the only approved therapy to address the underlying cause of LAL-D.

Long-term Benefit of Sebelipase Alfa Over 52 Weeks in Children and Adults With Lysosomal Acid Lipase Deficiency (ARISE Trial)1

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.

“We are encouraged by these study results, which show marked and sustained improvements in disease-related lipid and liver abnormalities in patients with LAL-D who were treated with Kanuma and highlight the need for long-term therapy for patients with this devastating and life-threatening disease,” said study investigator Katryn Furuya, M.D., Associate Professor of Pediatrics, Division of Pediatric Gastroenterology and Solid Organ Transplant, Mayo Clinic, Rochester, Minn. “Importantly, results for patients who initially received placebo before switching to Kanuma mirrored those of patients who received Kanuma from the start of the double-blind period, suggesting a consistent and reproducible treatment effect across a large group of treated patients.”

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.7

(Headline updated on 10-20-16)



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