Olipudase Alfa in Non-CNS Manifestations of Acid Sphingomyelinase Deficiency: A Profile of Its Use

Abstract

Olipudase alfa (Xenpozyme™) is an intravenously administered acid sphingomyelinase enzyme replacement therapy indicated to treat non-CNS manifestations of acid sphingomyelinase deficiency (ASMD) in adult and paediatric patients. It is the first and currently the only disease-modifying treatment for ASMD. Olipudase alfa treatment improves hepatosplenomegaly, lung function and platelet counts, along with multiple other pathological features of ASMD in adult and paediatric patients with ASMD. These benefits are sustained through at least 24 months of treatment. Olipudase alfa is generally well tolerated; infusion-associated reactions (mostly mild) were the most common treatment-related adverse events. Other warnings and precautions associated with its use include risks of hypersensitivity reactions (including anaphylaxis) and elevated transaminase levels seen in clinical trials, and foetal malformation based on animal studies. All these risks are generally manageable. A gradual dose escalation of olipudase alfa, followed by a maintenance phase, is required to reduce the risks of toxic sphingomyelin catabolites build up, infusion-associated reactions and transient transaminase elevations.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40261-023-01270-x.

Plain Language Summary

Sphingomyelin, a fatty substance found in mammalian cell membranes, is broken down by the enzyme acid sphingomyelinase in healthy individuals. Acid sphingomyelinase deficiency (ASMD) is a rare inherited genetic disorder, in which the patient’s body does not produce enough of the acid sphingomyelinase enzyme, leading to accumulation of sphingomyelin in major organs such as lungs, liver and spleen. ASMD types A and A/B (but not type B) also involve brain cells. Olipudase alfa (Xenpozyme™) is an enzyme replacement therapy indicated to treat non-CNS manifestations of ASMD in adult and paediatric patients. By reducing sphingomyelin accumulation, olipudase alfa improves lung function, reduces liver and spleen volume, and increases platelet counts, while also correcting other ASMD-related dysfunctions. These benefits are sustained through at least 24 months of treatment. Olipudase alfa is generally well tolerated. It is the first and currently the only disease-modifying treatment for ASMD.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40261-023-01270-x.

Digital Features for this Adis Drug Q&A can be found at https://doi.org/10.6084/m9.figshare.22281637.

Adis evaluation of olipudase alfa in non-CNS manifestations of ASMD

First and currently the only disease-modifying therapy

Improves lung function, reduces liver and spleen volume, and increases platelet counts; efficacy sustained through at least 2 years of treatment

Generally well tolerated

What is the Rationale for Developing Olipudase Alfa?

Sphingomyelin is an integral component of mammalian cell membrane and is hydrolyzed by the enzyme acid sphingomyelinase [1]. Acid sphingomyelinase deficiency (ASMD) [historically known as Niemann Pick disease types A and B] is a rare autosomal recessive lysosomal storage disorder caused by pathological sequence variants in the SMPD1 gene that encodes acid sphingomyelinase [2]. ASMD leads to progressive accumulation of sphingomyelin (and other lipids) in reticuloendothelial system-rich tissues, such as lung, spleen, liver, bone marrow and lymph nodes, and in severe cases, neurons [3]. ASMD exhibits a spectrum of clinical disease phenotypes, with three subtypes identified based on disease severity and neurological involvement: infantile neurovisceral ASMD (type A), chronic neurovisceral ASMD (type A/B; also known as intermediate form) and chronic visceral ASMD (type B) [3, 4]. While types A/B and B are slowly progressive, type A is rapidly progressive, severe and uniformly fatal [3, 4]. Across all subtypes, visceral manifestations of ASMD include interstitial lung disease (ILD), hepatosplenomegaly, progressive liver disease with cirrhosis and fibrosis, dyslipidaemia, thrombocytopenia, anaemia and osteopenia [4–8]. Growth restriction and delayed skeletal maturation are common in children with ASMD [9]. In patients with ASMD types A/B or B, respiratory failure, liver failure and bleeding are the leading causes of death [10]. Chronic forms of ASMD are associated with a substantial lifelong disease burden, increased mortality, decreased health-related quality of life (HRQOL) and increased healthcare use [4, 5, 7, 11].

Until recently, only supportive care was available for patients with ASMD and a corrective treatment remained an unmet medical need [3, 12]. Olipudase alfa (Xenpozyme™) is an intravenous infusion formulation of recombinant human acid sphingomyelinase produced in Chinese hamster ovary cells [13]. It is the first and currently the only disease-modifying enzyme replacement therapy for ASMD. Olipudase alfa is approved in more than 35 countries, including those in the EU [14], USA [15] and Japan [16], to treat non-CNS manifestations of ASMD in paediatric and adult patients. Table 1 provides a summary of the EU and US prescribing information for olipudase alfa.

Table 1.

Prescribing summary of olipudase alfa (Xenpozyme^®) in the treatment of non-CNS manifestations of acid sphingomyelinase deficiency in the EU [14] and USA [15]. Consult local prescribing information for further details

What is the approved indication of olipudase alfa?
EU: treatment of non-CNS manifestations of ASMD in adult and paediatric patients with type A/B or type B
USA: treatment of non-CNS manifestations of ASMD in adult and paediatric patients
How is olipudase alfa available and how should it be stored?
Available as: lyophilised powder in a 20 mg single-dose vial for reconstitution and dilution for intravenous infusion
Storage: refrigerate (do not freeze) original product at 2–8 °C; refrigerate reconstituted vials or diluted solutions (if not used immediately) at 2–8 °C for up to 24 h or store at room temperature (20–25 °C) for up to 12 h
What is the recommended administration regimen and method for olipudase alfa?
Dose-escalation phase	Adults: 0.1, 0.3, 0.3, 0.6, 0.6, 1 and 2 mg/kg at weeks 0, 2, 4, 6, 8, 10, and 12, respectively
	Paediatric patients: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1 and 2 mg/kg at weeks 0, 2, 4, 6, 8, 10, 12 and 14, respectively
Maintenance dose	3 mg/kg every 2 weeks from week 14 in adults and week 16 in paediatric patients
Administration method	Increase infusion ratea incrementally in four steps and only in the absence of infusion-associated reactions, with the first three steps lasting for 20 min
	Adjust infusion volumesa patients with acid sphingomyelinase based on patient age and/or body weight
How should olipudase alfa be used in special populations?
Patients with abnormal kidney function	No dosage adjustment required
Patients with abnormal liver function	No dosage adjustment required
Elderly patients	No dosage adjustment required (based on limited data)
Breastfeeding patients	It is not known whether olipudase alfa is excreted in human milk, but a risk to newborns cannot be excluded based on animal studies
	Discontinue breastfeeding or treatment based on benefits of breastfeeding for infant versus mother’s clinical need for treatment
What other special warnings/precautions pertain to the use of olipudase alfa?
Hypersensitivity reactions including anaphylaxis, infusion-associated reactions	Consider premedications (antihistamines, antipyretics, corticosteroids)
	Severe reaction: discontinue treatment and initiate appropriate medical treatment
	Mild or moderate reaction: adjust infusion rate, temporarily withhold infusion, or adjust dosage
Elevated transaminases	Monitor ALT and AST levels before and during treatment; adjust dosage based on transaminase levels or withhold treatment until levels return to baseline value
Risks during pregnancy	Do not initiate or escalate dosage at any time during pregnancy; base maintenance dosing decision on patient’s benefit-risk profile
	Advise women of reproductive potential to use effective contraception during and for 14 days after the last dose of treatment

ALT alanine aminotransferase, ASMD acid sphingomyelinase deficiency, AST aspartate aminotransferase, CNS central nervous system

^aConsult local prescribing information for the recommended infusion rates and volumes

What are the Pharmacological Properties of Olipudase Alfa?

Pharmacodynamic Properties

Olipudase alfa augments the deficient acid sphingomyelinase activity in patients with ASMD, thereby reducing sphingomyelin accumulation in various target tissues [17, 18]. The recombinant enzyme has a molecular weight of ≈ 75 kDa [13] and is not expected to cross the blood-brain barrier [19]; therefore, it has no clinical activity against CNS manifestations of ASMD. The pharmacodynamic activity of olipudase alfa was initially assessed in five adults with ASMD in a phase 1b trial [17, 20] and its long-term extension over up to 6.5 years [21–23]. Discussion in this section focuses mainly on larger clinical trials conducted in adult [24] and paediatric [25] patients with ASMD type A/B or B.

Lyso-sphingomyelin (a deacylated form of sphingomyelin) and chitotriosidase (an enzyme produced by activated macrophages) levels are elevated in patients with ASMD and they serve as pharmacodynamic biomarkers of response to olipudase alfa [24, 25]. Olipudase alfa treatment for 52 weeks was associated with a substantial reduction from baseline in mean pre-infusion plasma lyso-sphingomyelin levels (− 78% vs − 6.1% with placebo in adult patients [24]; − 87% in paediatric patients [15, 25]) and mean plasma chitotriosidase levels (− 54.7% vs − 12.3% with placebo in adult patients, nominal p = 0.0003 [24]; − 58% in paediatric patients [25]). The levels of both biomarkers were nearly normalized at 24 months in paediatric patients [26].

Adult patients treated with olipudase alfa showed a decrease in accumulation of sphingomyelin in the liver, as assessed by histopathology [20, 22, 24]. In a phase 2/3 trial, the mean percent change from baseline at 52 week was − 92.7% in olipudase alfa recipients, compared with + 10.9% in placebo recipients [24]. Liver sphingomyelin clearance during olipudase alfa treatment was associated with improved lipid profiles [22, 24, 27].

Dose Escalation

Accumulation of excessive ceramide, a catabolite of sphingomyelin, is associated with a cytokine release syndrome [28]. A single high dose (≥ 10 mg/kg) of olipudase alfa in acid sphingomyelinase knockout mice resulted in unexpected toxicity (cardiovascular shock, liver inflammation, adrenal haemorrhage, death) that could be attributed to rapid breakdown of large amounts of sphingomyelin into ceramide and/or other toxic downstream metabolites. The toxicity was prevented by administration of several small doses to gradually debulk accumulated sphingomyelin, prior to high doses [28].

These findings were confirmed in patients with ASMD. In a phase 1 single-ascending-dose study in 11 adult patients with ASMD type B, olipudase alfa ≥ 0.3 mg/kg increased plasma ceramide levels by up to 5-fold in a dose- and time-dependent manner, starting between 2 and 6 h post-infusion [18]. Four of five patients who received ≥ 0.3 mg/kg doses developed an acute phase reaction starting at 12 h, characterised by elevated proinflammatory biomarkers, such as interleukin-8, calcitonin and high-sensitivity C-reactive protein, and constitutional symptoms, such as fever, pain, nausea and/or vomiting. The maximum tolerated starting dose of olipudase alfa was 0.6 mg/kg [18].

In a subsequent phase 1b proof-of-concept study in five adult patients with ASMD, a within-patient olipudase alfa dose-escalation strategy (0.1, 0.3, 0.3, 0.6, 1.0, and 2.0 mg/kg on weeks 0, 2, 4, 6, 8 and 10, respectively, followed by a maintenance dose of 3.0 mg/kg once every 2 weeks) gradually debulked accumulated sphingomyelin, mitigating the toxicity associated with rapid production of sphingomyelin catabolites [17]. The 3.0 mg/kg dose was selected as the targeted maintenance dose to maximize olipudase alfa penetration into hard-to-reach target organs, such as lungs. All patients successfully escalated to the target dose of 3.0 mg/kg and completed 26 weeks of treatment, with no serious or severe adverse events (AEs) [17].

The debulking/dose-escalation strategy developed in the phase 1b trial was adapted in the subsequent larger ≥ 52-week clinical trials in adult [24] and paediatric [25] patients with ASMD, with minor changes: a second 0.6 mg/kg dose was added to the dose-escalation protocol for both adult and paediatric patients, and a lower starting dose of 0.03 mg/kg was added to the protocol for paediatric patients as a safety precaution in young children. Mean plasma ceramide levels transiently increased after each olipudase alfa infusion; however, both pre- and post-infusion plasma ceramide levels decreased at each dose-escalation step and after reaching the maintenance dose [24, 25]. The normal range of plasma ceramide is 1.3–3.3 mg/L. In adult patients, the mean pre-infusion plasma ceramide level was 3.7 mg/L at baseline and 2.2 mg/L at 52 weeks [24]. The corresponding levels in paediatric patients were 4.7 and 1.8 mg/L, respectively [25]. While there were no acute phase reactions in adults [24], 3 of 20 paediatric patients experienced such reactions during dose escalation and were managed with dosage adjustment at the next infusion [25].

A dose-escalation regimen also helps to reduce the risk of hypersensitivity reactions, infusion-associated reactions (IARs) and elevated transaminase levels typically seen with olipudase alfa infusion [14, 15]. Therefore, olipudase alfa prescribing information recommends a gradual dose-escalation regimen (Table 1).

Pharmacokinetic Properties

Following intravenous administration, olipudase alfa plasma concentrations increased in a dose-proportional manner over a dose range of 0.03–3 mg/kg, with no apparent relationship between dose and terminal half-life, clearance or volume of distribution at steady state [17, 18]. With repeated administrations, accumulation of olipudase alfa in plasma was minimal [14, 15]. In adult patients, the mean volume of distribution of olipudase alfa was 13 L, mean clearance was 0.331 L/h and the mean terminal half-life was 32–38 h [14, 15]. The corresponding values for paediatric patients were 153–172 mL/kg, 6.2–6.8 mL/h/kg and 23–24 h, respectively [25]. Olipudase alfa is expected to be eliminated through proteolytic degradation into small peptides and amino acids [14, 15]. Consequently, liver or kidney function impairment is unlikely to affect the pharmacokinetics of this drug. There were no clinically relevant differences in olipudase alfa exposure based on gender, ethnicity (Asian or Caucasian) or old age (65–75 years) [14, 25]. Being a recombinant protein, olipudase alfa is unlikely to induce cytochrome P450 mediated drug-drug interactions [1].

What is the Clinical Efficacy of Olipudase Alfa?

This section focuses on the efficacy of olipudase alfa in patients with ASMD types B or A/B as evaluated in a randomized, double-blind, placebo-controlled, multicentre, 52-week, phase 2/3 trial in adults (ASCEND) [24], an open-label, single-arm, multicentre, 64-week, phase 1/2 trial in paediatric patients (ASCEND-Peds) [25] and their long-term extensions (LTEs) [26, 27]. ASCEND-Peds was primarily a safety trial, with efficacy endpoints assessed at 52 weeks in an explorative manner [25]. In both trials, ASMD types B and A/B were not differentiated. Olipudase alfa was administered once every 2 weeks following a dose-escalation scheme (Table 1) that differed slightly between adult and paediatric patients [24, 25]. The final target maintenance dose was 3 mg/kg in both age groups, with dosing schedules adjusted according to tolerability and prespecified dose-limiting toxicity criteria, based on aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL) levels [24, 25]. Olipudase alfa also showed preliminary efficacy in five adult patients with ASMD type B in the phase 1b trial discussed in Sect. 2.1, the results of which are not discussed further.

ASCEND

In ASCEND, eligible patients had ASMD confirmed by enzymatic assay and/or genotyping, lung diffusing capacity for carbon monoxide (DL_CO) ≤ 70% of predicted normal value, spleen volume ≥ 6 multiples of normal (MN) and splenomegaly-related score (SRS) ≥ 5 [24]. SRS is a patient-reported outcome (PRO) adapted from a subset of assessments used for myelofibrosis that measures the impact of five splenomegaly-related discomforts (abdominal pain, abdominal discomfort, early satiety, abdominal body image and ability to bend down) on patient quality of life on a scale of 0 (absent) to 10 (worst imaginable). SRS is not validated in ASMD and was used for this condition for the first time in the ASCEND trial. Patients with mean platelet count < 60 × 10⁹/L, ALT or AST > 250 IU/L, or TBIL > 1.5 mg/dL were among those excluded [24].

Patients received olipudase alfa or placebo for 52 weeks [24]. The primary endpoints were % predicted DL_CO and spleen volume (spleen volume plus SRS in the USA). Secondary endpoints included liver volume, platelet counts and PROs, including Brief Fatigue Inventory (BFI), Brief Pain Inventory (BPI), and Functional Assessment of Chronic Illness Therapy-Dyspnea (FACIT-Dyspnea). Endpoints were assessed following a statistical hierarchy. Comparative efficacy results presented in this section are least squares mean (LSM) percent change from baseline at 52 weeks in olipudase alfa versus placebo groups, unless stated otherwise [24].

Patient demographics and baseline characteristics were generally balanced between the olipudase alfa and placebo groups, except for the proportion of women (50% vs 72%) and mean age at ASMD diagnosis (21.4 vs 14.6 years) [24]. At baseline, patients had moderate impairment in lung diffusing capacity (mean % predicted DL_CO ≈ 49%) and moderate to severe splenomegaly (mean spleen volume 11–12 MN) across groups. Mean treatment compliance was 95% in both groups [24].

Olipudase alfa treatment significantly improved % predicted DL_CO and spleen volume versus placebo (Table 2), with no significant between-group difference for SRS (primary endpoints) [24]. The improvements in the olipudase alfa group were seen at the first assessment timepoint (week 26) [nominal p ≤ 0.0015 vs placebo]. In prespecified analyses, more olipudase alfa than placebo recipients had a ≥ 15% absolute increase in % predicted DL_CO (27.7% vs 0% patients) and a ≥ 30% reduction in spleen volume (94.4% vs 0% patients) at week 52 [24].

Table 2.

Efficacy of olipudase alfa in patients with acid sphingomyelinase deficiency types B or A/B

Treatment (no. of pts)	LSM percent change from baseline to week 52 [baseline values]
	% predicted DLCOa	Spleen volumea	Liver volume	Platelet count
In randomized, double-blind, phase 2/3 ASCEND trial in adult pts [24]
Olipudase alfa (18)	+ 21.97 [49.4 %]	− 39.45 [11.7 MN]	− 28.06 [1.4 MN]	+ 16.82 [107.2 × 109/L]
Placebo (18)	+ 2.96 [48.5%]	+ 0.48 [11.2 MN]	− 1.47 [1.6 MN]	+ 2.49 [115.6 × 109/L]
Difference	+ 19.0**	− 39.9***	− 26.6***	+ 14.3*
In single-arm, open-label, phase 1/2 ASCEND-Peds trial in paediatric pts [25]
Overall (20)	+ 33†† [54.8%]	− 49.2††† [19 MN]	− 40.6††† [2.7 MN]	+ 34.03††† [137.4 × 109/L]
Adolescent (4)	+ 28b	− 46.9†††	− 41††b	+ 45.01 [98.93 × 109/L]
Child (9)	+ 35††b	− 46.0†††	− 37†††b	+ 30.67† [148.82 × 109/L]
Infant/early child (7)	NA	− 54.6†††	− 45†††b	+ 31.76† [145.66 × 109/L]

DL_CO lung diffusing capacity for carbon monoxide, LSM least squares mean, MN multiples of normal, NA not applicable, pts patients, SRS splenomegaly-related score

*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo; ^†p ≤ 0.05, ^††p ≤ 0.01, ^†††p ≤ 0.001 vs baseline

^aPrimary endpoints. In the USA, the spleen endpoint was spleen volume combined with SRS (see main text for SRS description); there was no significant difference between olipudase alfa and placebo group for SRS at week 52

^bData extracted from graph

In addition to DL_CO, olipudase alfa treatment was associated with improvements in other pulmonary endpoints versus placebo, including high-resolution computed tomography (HRCT) mean scores for ILD (− 0.36% vs + 0.09%) and ground glass appearance (− 0.49% vs + 0.18%), chest X-ray interstitial mean score (− 0.91% vs + 0.28%) and mean % predicted forced vital capacity (FVC; + 6.76% vs + 1.48%) [nominal p < 0.05 for all] [24]. There were no significant between-group differences in forced expiratory volume in the first second (FEV1) and total lung capacity [24].

Olipudase alfa treatment decreased liver volume and increased platelet counts versus placebo (Table 2) [24]. Furthermore, levels of ALT (− 36.5% vs − 0.98%), AST (− 31.6% vs + 2.0%) and TBIL (− 29.9% vs + 12.5%) decreased in the olipudase alfa group relative to the placebo group (nominal p = 0.006 for all) [24].

Patients treated with olipudase alfa had an increase in antiatherogenic lipids/proteins [apolipoprotein A1, high-density lipoprotein cholesterol (HDL-C)] and a reduction in proatherogenic lipids/proteins, such as apolipoprotein B, non-HDL-C, low-density lipoprotein cholesterol (LDL-C) and triglycerides (nominal p values < 0.001 vs placebo for all) [24].

There were no significant differences between olipudase alfa and placebo groups for PROs of BFI, BPI and FACIT-Dyspnea, or for additional PROs of 36-Item Short Form Health Survey (SF-36) and EQ-5D-5L [24].

All patients who completed the 1-year primary analysis crossed over to the ongoing open-label LTE [27]. Patients who received a second year of olipudase alfa treatment (n = 18) had continued clinical improvement. LSM percent change from baseline at 2 years in these patients were: % predicted DL_CO − 28.5%, spleen volume − 47.0%, liver volume − 33.4%, platelet counts + 24.9%, ALT − 32.0%, HDL-C + 64.4% and LDL-C − 23.0%. Patients who switched from placebo to olipudase alfa (n = 17) in the LTE achieved clinical improvements at 1 year that were of the same magnitude as those seen in olipudase alfa recipients at 52 weeks in the primary analysis period [27].

ASCEND-Peds

Eligible patients in ASCEND-Peds had confirmed ASMD, spleen volume ≥ 5 MN and height z-score − 1 or less [25]. Exclusion criteria included: mean platelet count < 60 × 10⁹/L; ALT or AST > 250 IU/L, TBIL > 1.5 mg/dL or international normalized ratio > 1.5; and neurological abnormalities and/or certain ASMD type A genotypes. Participants were recruited sequentially in three cohorts: adolescents (12 to < 18 years; n = 4), children (6 to < 12 years; n = 9) and infants/early child (< 6 years; n = 7). Median age at symptom onset was 1.28, 1.19 and 0.99 years in the respective cohorts. Patients received olipudase alfa for 64 weeks, after which they continued treatment in a long-term study. As efficacy assessments in ASCEND-Peds were exploratory, all statistical significance is nominal [25].

Pulmonary endpoints were assessed only in patients aged ≥ 5 years who were able to perform the test [25]. At week 52, DL_CO significantly increased in nine evaluable patients (Table 2). At baseline, one, four and four patients had severe, moderate, and mild DL_CO impairment, respectively. At 52 weeks, DL_CO improved in all but two patients with mild severity in the child cohort. In 13 evaluable patients, mean values of % predicted FVC increased from 77.5% at baseline to 85.7% at week 52, FEV1 from 76.5% to 81.7% and total lung capacity from 86.8% to 110.2%. HRCT ILD scores decreased from baseline by 13%, 23% and 24% in the adolescent, child, and infant/early child cohorts, respectively. Six cases of severe ILD at baseline improved to mild or moderate in five cases and resolved in one [25].

At baseline, all patients had moderate or severe splenomegaly and hepatomegaly [25]. After 52 weeks of olipudase alfa treatment, spleen and liver volume significantly decreased in the overall population, with similar results seen in all three age cohorts (Table 2). Statistically significant decreases in spleen and liver volumes were seen at the first assessment timepoint (week 26). All 10 patients who had severe hepatomegaly at baseline improved to moderate hepatomegaly at week 52. Mean transaminase levels were elevated at baseline and were normalized at 52 weeks. The mean percent change from baseline at 52 weeks was – 51.9% for AST and – 59.4% for ALT. At baseline, 80% of patients had abnormal AST or ALT and at week 52, 10.5% and 10% of patients had abnormal AST and ALT, respectively [25].

At 52 weeks, platelet counts increased significantly in the overall population and in the children and infant/early child cohorts (Table 2) [25]. Mean plasma lipid (total cholesterol, triglycerides, HDL-C, LDL-C) levels were outside the normal range at baseline; the levels improved by week 26 and returned to normal range by week 52. LSM height z-scores significantly increased from baseline at week 52 in the overall population (p < 0.0001), and in the child and infant/early child cohorts (p < 0.05 for both) [25].

All 20 patients who completed the primary analysis. continued olipudase alfa treatment through at least 24 months in an ongoing long-term study [26]. The clinical improvements seen at 12 months were sustained or further improved at 24 months. LSM percent change from baseline at month 24 were: % predicted DL_CO + 46.6%; spleen volume − 60.9%; liver volume − 49.0%; platelet counts + 35.9 × 10⁹/L (p ≤ 0.0014 vs baseline for all). Significant (p < 0.05) improvements from baseline at 24 months were also seen in FVC (+ 22.6%), total lung capacity (+ 22.8%), ILD score (− 0.70 points), ground glass appearance score (− 0.44 points), reticulonodular density score (− 0.58 points), ALT (− 64.4%), AST (− 56.0%), TBIL (− 45.3%), total cholesterol (− 26.0%), triglycerides (− 56.2%), LDL-C (− 34.8%), HDL-C (+ 137%), and height z-score + 1.17 [26].

What is the Tolerability of Olipudase Alfa?

Olipudase alfa was generally well tolerated in the 52-week ASCEND trial in adult patients [24] and the 64-week ASCEND-Peds trial in paediatric patients [25] with ASMD type B or A/B, with no new safety issues seen during the LTEs through 24 months [26, 27]. At least one treatment-emergent AE (TEAE) occurred in all adult patients receiving olipudase alfa (n = 18) or placebo (n = 18) through week 52 (242 vs 270 events), and all paediatric patients receiving olipudase alfa (n = 20) through week 64 (798 events). However, 79% and 88% of TEAEs with olipudase alfa in adult and paediatric patients, respectively, were mild in severity; no patient in either study discontinued treatment because of AEs. During dose escalation in the primary analyses, temporary dose reduction was required in one adult patient (5.6%) and seven paediatric patients (35%) receiving olipudase alfa; all patients subsequently achieved the target dose of 3 mg/kg [24, 25].

In adult patients, at 52 weeks, 66.7% of 18 olipudase alfa and 33.3% of 18 placebo recipients experienced TEAEs potentially related to study treatment, many of which in the olipudase alfa group were IARs [24]. The most common (incidence ≥ 10%) treatment-related AEs in olipudase alfa recipients were headache (44.4% vs 16.7% of placebo recipients), nausea (11.1% vs 16.7%), abdominal pain (11.1% vs 0%), musculoskeletal chest pain (11.1% vs 0%), myalgia (11.1% vs 0%) and pyrexia (11.1% vs 0%). Serious AEs occurred in three olipudase alfa recipients (16.6%) and four placebo recipients (22.2%); none were considered treatment-related [24].

In paediatric patients (n = 20), at 64 weeks, the most common (incidence ≥ 25%) TEAEs with olipudase alfa were pyrexia (75%), cough (70%), vomiting (60%), nasopharyngitis (55%), diarrhoea (55%), upper respiratory tract infection (40%), nausea (40%), headache (40%), gastroenteritis (40%), rhinitis (35%), contusion (30%), abdominal pain (30%), nasal congestion (30%), rash (30%), fall (30%), oropharyngeal pain (30%), upper abdominal pain (25%) and ear pain (25%) [25]. Treatment-related TEAEs (many of which were IARs) occurred in 56% of patients. Serious AEs occurred in five (25%) patients; three (15%) patients experienced five treatment-related serious AEs (anaphylactic reaction in one patient, two instances of transient asymptomatic ALT increase in one patient, and urticaria and rash in another patient) [25].

Special Warnings and Precautions

IARs, which typically occurred 12–72 h after olipudase alfa infusion, were reported in 44.4% of adult [24] and 55% of paediatric [25] patients. There were no severe or serious IARs to olipudase alfa in adults and 88% of IARs in paediatric patients were mild in severity [24, 25]. Headache (27.8%) and nausea (11.1%) were the two most common IARs in adults [24]. The most frequent IARs (incidence ≥ 15%) in paediatric patients were pyrexia (35%), vomiting (30%), urticaria (20%), headache (20%), increased C-reactive protein (20%), nausea (20%), increased serum ferritin (15%) and rash (15%) [25]. IARs were managed with premedication and/or temporary infusion interruptions and dose reductions [24, 25]. Premedications, while not routinely required, may be given to reduce the risk of IARs to olipudase alfa [14, 15].

Hypersensitivity reactions (in one adult patient), including anaphylaxis (in one paediatric patient), have been reported in olipudase alfa recipients [24, 25]. Hypersensitivity reactions included urticaria, pruritus, erythema, rash, erythematous rash, eczema, angioedema and erythema nodosum in adults, and urticaria, pruritus, rash, erythema and localized oedema in paediatric patients [14, 15]. In the patient with anaphylactic reaction, a desensitization regimen of olipudase alfa allowed continuation of treatment [25]. The US prescribing information carries a boxed warning on the risk of severe hypersensitivity reactions to olipudase alfa [15]. When such reactions occur, olipudase alfa treatment should be discontinued immediately, with appropriate medical treatment initiated [14, 15].

Transaminase levels may be elevated within 24–48 h after olipudase alfa infusion, although the levels typically returned to pre-infusion levels at the time of the next infusion [14, 15]. In the ASCEND and ASCEND-Peds trials, one adult (5.6%) and six paediatric (30%) patients had an increase in AST, ALT, TBIL or ALP levels that met the criteria for dose-limiting toxicity [24, 25]. As recommended in the drug labels, the risk of transient elevations in liver enzymes can be managed by monitoring AST/ALT levels before and during treatment with olipudase alfa and dosage modification [14, 15].

There are no data on use of olipudase alfa during pregnancy; however, due to animal studies suggesting reproductive toxicity, initiation or dose escalation of olipudase alfa is not recommended at any time during pregnancy and women who can become pregnant are advised to use contraception during and up to 14 days after the last dose of olipudase alfa [14, 15].

Immunogenicity

As with all therapeutic proteins, olipudase alfa has the potential for immunogenicity [24, 25]. In ASCEND, olipudase alfa induced immunoglobulin (Ig) G anti-drug antibodies (ADAs) in 4 of 16 (25%) adult patients who were ADA-negative at baseline; in two patients who were ADA-positive at baseline, there was no treatment-boosted ADA response [24]. In ASCEND-Peds, ADAs were detected in 12 of 20 (60%) paediatric patients treated with olipudase alfa; two of these patients were ADA-positive at baseline, one with a titre 50 and another with no treatment-induced changes in ADA status [25]. Most ADA-positive patients had a low-titre (≤ 400) response [24, 25]. One exception was the paediatric patient with anaphylactic reaction who had developed IgG and IgE ADAs, with a peak titre of 1600 (i.e. intermediate response) [14, 25]. Although ADAs generally had no effect on pharmacokinetics or efficacy of olipudase alfa, IARs tended to be more frequent in those who developed ADAs than in those who did not (incidence 75.9% vs 41.9%) [14].

What is the Current Clinical Position of Olipudase Alfa?

Enzyme replacement therapy with olipudase alfa is the first, and currently the only, disease-modifying treatment available for ASMD. This condition is historically managed with supportive and palliative care, including antibiotics, bronchodilators, calcium supplements, fresh plasma, statins, supplemental oxygen, growth hormones, and cell and organ transplantation, with some of these interventions (e.g. organ transplantation) presenting their own safety risk [12]. The recent availability of olipudase alfa fills a hitherto unmet medical need in ASMD.

Olipudase alfa reduces sphingomyelin accumulation in tissues and thereby produces clinically meaningful improvements in multiple pathological features of ASMD. Organomegaly, especially splenomegaly, and lung disease are independent contributors of mortality, morbidity and disease burden in patients with chronic forms of ASMD [29]. Abnormal bleeding, presumably related to thrombocytopenia at least in part, is also a common symptom in these patients [5]. In clinical trials, olipudase alfa treatment for 52 weeks significantly reduced spleen and liver volumes, and significantly increased % predicted DL_CO and platelet counts in adult and paediatric patients with ASMD types A/B or B. It also improved growth in paediatric patients. The efficacy of olipudase alfa was sustained or further improved through 24 months of treatment. These findings are supported by real-world experience of olipudase alfa treatment in two Taiwanese children with type A/B ASMD [30].

Olipudase alfa is generally well tolerated in patients with ASMD, with the most common treatment-related AEs being IARs, most of which are of mild severity. The bioactivity of this enzyme (hydrolysis of sphingomyelin) leads to a transient increase in plasma levels of ceramide, a potentially toxic sphingomyelin catabolite. A within-patient dose-escalation strategy that gradually debulks the accumulated sphingomyelin minimizes this toxicity and helps achieve a clinically effective maintenance dose (3 mg/kg once every 2 weeks). In order to manage potential adverse reactions, olipudase alfa treatment should be administered by a healthcare professional in a clinical setting [31]. However, if patients tolerate their infusions well, maintenance doses may be administered in a home setting under the supervision of a healthcare provider [14, 15]. Other warnings and precautions associated with the use of olipudase alfa include risks of hypersensitivity reactions (including anaphylaxis) and elevated transaminase levels seen in clinical trials, and potential foetal toxicity based on animal studies. Overall, the enzyme replacement therapy has a positive benefit-risk profile in patients with ASMD.

There are a few uncertainties and limitations about the clinical use of olipudase alfa. ASMD has a huge negative impact on patient HRQOL [5]. First, in clinical trials, the functional improvements seen with olipudase alfa treatment do not appear to correlate well with patient-reported HRQOL improvements, although some of the instruments administered (such as SRS and FACIT-Dyspnea) are not specifically validated in patients with ASMD. Next, the paediatric trial (ASCEND-Peds) was not a controlled study and had a relatively small sample size due to the rarity of the disease; however, when its efficacy results (which are explorative only) are considered together with those of the placebo-controlled adult trial (ASCEND), compelling evidence for the efficacy of olipudase alfa emerges. Finally, ASMD requires lifelong treatment and cost may be an important determinant of treatment choice; the cost effectiveness of olipudase alfa remains to be studied.

While there are consensus recommendations for the diagnosis [3] and clinical monitoring [32] of patients with ASMD, there are currently no formal guidelines for the management of this rare condition. A preprint version of consensus clinical management guidelines for ASMD is now available [33], the peer-reviewed version of which is awaited with interest in the context of olipudase alfa’s place in ASMD management.

Supplementary Information

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Declarations

Funding

The preparation of this review was not supported by any external funding.

Authorship and Conflict of interest

Yahiya Y. Syed is a salaried employee of Adis International Ltd/Springer Nature and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.

Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability

Not applicable.