Sebelipase alfa for lysosomal acid lipase deficiency: 5‐year treatment experience from a phase 2 open‐label extension study

Abstract Background and Aims Lysosomal acid lipase deficiency is characterized by hepatomegaly and dyslipidaemia, which can lead to cirrhosis and premature atherosclerosis. Sebelipase alfa is an approved recombinant human lysosomal acid lipase. In an open‐label extension study of adults with lysosomal acid lipase deficiency (LAL‐CL04), sebelipase alfa treatment for 1 year reduced serum transaminase levels and liver fat content and improved serum lipid levels. Methods Final data from LAL‐CL04 are reported herein for patients who received sebelipase alfa infusions (1.0 or 3.0 mg/kg every other week) for up to 5 years. Results Of 8 patients enrolled, 7 received sebelipase alfa for 224‐260 weeks; 1 was lost to follow‐up. Median baseline levels of alanine aminotransferase and aspartate aminotransferase (81.5 and 50.0 U/L, respectively) were decreased through the end‐of‐study visit (54.0 and 34.0 U/L). Median low‐density lipoprotein cholesterol decreased from 113 to 78 mg/dL, total cholesterol decreased from 171 to 132 mg/dL, and high‐density lipoprotein cholesterol increased from 37 to 42 mg/dL. Most treatment‐emergent adverse events were nonserious (99%), mild/moderate (98%) and unrelated to sebelipase alfa (87%); no patient discontinued as a result of treatment‐emergent adverse events. One patient had 2 serious treatment‐emergent adverse events (cholecystitis and cholelithiasis; assessed as unlikely related to sebelipase alfa). Two patients had 20 nonserious infusion‐associated reactions in weeks 6‐38; all were manageable. One patient tested positive for antidrug antibodies (single occurrence). Conclusions Sebelipase alfa was well tolerated and improved serum transaminase and lipid levels for up to 5 years in adults with lysosomal acid lipase deficiency. Trial registration number: ClinicalTrials.gov record NCT01488097.


| INTRODUC TI ON
In lysosomal acid lipase (LAL) deficiency, functional mutations in the LIPA gene lead to a complete or nearly complete absence of LAL activity. The consequence is lysosomal accumulation of triglycerides and cholesteryl esters in a variety of cell types and tissues (eg hepatocytes, macrophages, endothelial cells). [1][2][3][4] Diagnosis is confirmed by measuring LAL activity in dried blood spots, leukocytes or fibroblasts. 1,3,[5][6][7] The clinical sequelae of LAL deficiency in children and adults vary, and may include liver disease with hepatomegaly, elevated serum transaminases, microvesicular steatosis and fibrosis or cirrhosis. 4,8 Altered lipid metabolism leads to elevated low-density lipoprotein cholesterol (LDL-C) levels and low high-density lipoprotein cholesterol (HDL-C) levels, with accelerated vascular disease of variable degree. 1,3,4,9,10 Dietary modification and lipid-modifying medications are not effective in treating and preventing the progression of disease and neither addresses the underlying pathology. Liver transplantation is not well studied in this population and is associated with numerous complications, including the need for further transplantation. 3,4,8,11 Sebelipase alfa (SA) is a recombinant human enzyme replacement therapy indicated for the treatment of patients with LAL deficiency. 12,13 In the first human study of SA (LAL-CL01), a phase The objective of this analysis was to assess the efficacy and safety of SA for the treatment of adults with liver dysfunction as a result of LAL deficiency who received SA for up to 5 years in study LAL-CL04.

| Patients
Eligibility criteria for LAL-CL01 were described previously. 14 Patients eligible for LAL-CL04 were men and women ≥18 years of age who received all 4 scheduled doses of SA in study  with no life-threatening or unmanageable toxicity; patients were willing and able to comply with study procedures and provided written informed consent. Females were required to have a negative serum pregnancy test result at screening, were not breastfeeding and agreed to use an approved contraceptive method from the time of informed consent until 30 days after the last SA dose. Patients were excluded for clinically significant concurrent disease, serious intercurrent illness, use of concomitant medications or extenuating circumstances that, in the opinion of the investigator, would interfere with participation or interpretation of results. Patients were also excluded for clinically significant abnormal values on laboratory screening tests other than liver function or lipid panel tests. infused over approximately 2 hours. Infusions were administered at the study site or an approved local medical centre. Patients in the United States who were on a stable dose of SA for at least 12 months with no infusion-associated reactions (IARs) that required medical intervention or management and no treatment-related serious adverse events during the prior 6 months were eligible to receive infusions at home. Patients approved for home infusion were to return to the study site for scheduled assessments. Treatment duration in LAL-CL04 was up to 5 years. The last follow-up visit was approximately 30 days after the last SA dose.

| Study design
Dose increases from 1.0 mg/kg to 3.0 mg/kg qow and from 3.0 mg/kg qow to 3.0 mg/kg qw were allowed for inadequate clinical response (defined as clinically important LAL deficiency manifestations on clinical examination, laboratory assessment, liver biopsy or imaging that did not improve from baseline, improved and plateaued

Key points
• Lysosomal acid lipase (LAL) deficiency is a rare, inherited lysosomal storage disorder that can affect people of all ages and has a highly variable clinical presentation.
• Sebelipase alfa, a recombinant human LAL approved for the treatment of LAL deficiency, improves markers of liver cell injury and LAL deficiency-related lipid abnormalities; in infants, who have the most rapidly progressive form of the disease, sebelipase alfa prolongs survival.
• This study evaluated the efficacy and safety of sebelipase alfa in adults with liver dysfunction as a result of LAL deficiency who were treated for up to 5 years. but did not normalize, or failed to normalize within 12 months of treatment initiation). Patients who did not tolerate their SA dose could receive a dose reduction to the next lowest level (from 3.0 to 1.0 mg/kg qow; from 1.0 to 0.35 mg/kg qow) at the investigator's discretion. If a patient did not tolerate 0.35 mg/kg qow, despite measures to manage IARs, the patient was discontinued from the study.
The study was conducted according to the International Council for Harmonisation Good Clinical Practice guidelines. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and received a priori approval by each institution's human research committee in agreement with local legal requirements. The authors followed the STROBE cohort guidelines in reporting this study. 16

| Efficacy assessments
Absolute changes from baseline in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated. Optional liver biopsies were obtained where possible for hepatic histology evaluation between weeks 52 and 104. If a patient had a liver biopsy prior to screening, available results were recorded in the electronic case report form. Pathology reports for biopsies performed prior to treatment were also provided, if available.

| Safety assessments
The incidence of treatment-emergent adverse events (TEAEs), serious adverse events and IARs was determined. Adverse event (AE) severity was graded on a 5-point scale (mild, moderate, severe, life-threatening and death) according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
All AEs were coded using the Medical Dictionary for Regulatory Activities, version 20.0. IARs were defined as any AE that occurred during the 2-hour infusion or within 4 hours after the infusion and was assessed as at least possibly related to the study drug.
Testing for antidrug antibodies (ADAs) was routinely performed for all patients, and any patient who tested positive was subsequently tested for the presence of neutralizing antibodies that inhibit SA enzyme activity and/or cellular uptake. Analysis of ADAs and neutralizing antibodies was performed by a central laboratory (Covance). Vital signs were measured; blood and urine samples were collected for clinical laboratory evaluations; a complete physical examination was conducted and 12-lead electrocardiograms (ECGs) were obtained at various times throughout the study.  which they transitioned to commercial therapy; 1 patient was lost to follow-up after week 150 (the patient dropped out pending attempts to conceive a child). 15 The first study participant entered the extension study on December 12, 2011 and the last participant completed the study on June 21, 2017. All 8 patients initiated treatment between approximately 9 and 28 weeks after their last dose in study LAL-CL01. All were white, 6 were men and 7 were nonobese (body mass index <30.0 kg/m 2 ). As previously reported, 15 1 patient who completed LAL-CL01 did not decide to participate in LAL-CL04 until 10 months after completing therapy with sebelipase alfa in LAL-CL01. During this 10-month off-treatment period, the patient experienced worsening liver disease with evidence of hepatic decompensation and required urgent liver transplantation. These complications made the patient ineligible for LAL-CL04. Baseline demographic and disease characteristics of the 8 patients who were enrolled in LAL-CL04 are summarized in Table 1.

| Serum transaminases
Improvements in serum ALT and AST levels were maintained through the end-of-study visit. Table 2 shows absolute values at baseline and end of study and changes from baseline to end of study.

| Serum lipids
Improvements in serum lipids were also sustained with SA treatment. Absolute values at baseline and end of study and changes from baseline to end of study are shown in Table 2

| Liver volume and fat content
Liver volume and fat content decreased from baseline to week 208 (the last assessment at which data were available for >2 patients).
Absolute values at baseline and week 208 and changes from baseline to week 208 are shown in Table 2    The median change in spleen fat content from baseline to week 208 was −0.68% (range, −0.68% to 0.43%; n = 3 patients with paired data).

| Other parameters
Regarding other liver biochemical parameters, although the median serum GGT level decreased from baseline (29.5 U/L) at week 4 (median change, −5.5 U/L) and through the end of the study (median

| Liver biopsies
Two patients underwent pre-and post-treatment liver biopsies. The

| Infusions and concomitant medications
During the extension study, 920 infusions were administered to

| Immunogenicity
One patient tested positive for ADAs at a single time point (week 4), with a low titre of 80. This result was considered unlikely to represent a true seroconversion because the patient's subsequent ADA test results were negative. This patient also tested negative for neutralizing antibodies in both the enzyme activity and cell uptake assays. No IARs or other treatment-related TEAEs were reported for this patient; thus, no conclusions can be made regarding the impact of ADAs on the safety profile of SA.

| Changes in vital signs, physical examination findings, clinical laboratory tests, and ECG parameters
No clinically meaningful trends were observed in systolic or diastolic blood pressure, heart rate, respiratory rate or body temper- The interval between completion of study LAL-CL01 and enrolment for the 8 patients in this study ranged from 9 to 28 weeks, and during that time off treatment, increases in serum transaminases and LDL-C and decreases in HDL-C were observed relative to levels at the end-of-study LAL-CL01, 15 highlighting the benefit of continuous SA treatment. As previously reported, the 1 patient who did not participate in LAL-CL04 experienced rapidly progressive liver dysfunction requiring urgent liver transplantation during the 10 months after completing study LAL-CL01, 15  In conclusion, in adults with LAL deficiency, the early and rapidly achieved beneficial effects of SA were maintained throughout 5 years of treatment, with substantial and sustained improvements in serum transaminases, lipid abnormalities, and liver volume and fat content. Treatment with SA for up to 5 years was generally well tolerated. These findings support the long-term efficacy and safety of SA treatment in adults with LAL deficiency.

ACK N OWLED G EM ENTS
Editorial and medical writing support was provided by Jessica D.
Herr, PharmD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ and was funded by Alexion Pharmaceuticals, Inc, the study sponsor. In collaboration with the study sites, the sponsor designed and conducted the study, collected the data, monitored conduct of the study and performed the statistical analyses. The interpretation of the data was performed by the sponsor in collaboration with all of the authors. Alexion Pharmaceuticals, Inc provided review of this manuscript for the authors' consideration.

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