Introduction Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). Methods Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). Results Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: –72.7%, P < 0.001) and remained statistically significant at last observation (−62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. Conclusions Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints. . . . Keywords Alpha-mannosidosis Recombinant human alpha-mannosidase Lysosomal storage disorder Enzyme replacement . . therapy Velmanase alfa Integrated analysis Introduction Alpha-mannosidosis (AM) is a rare autosomal recessive lyso- somal storage disorder with an estimated prevalence of one in Communicated by: Carla E. Hollak 500,000–1,000,000 live births (Meikle et al 2004;Meikle etal Electronic supplementary material The online version of this article 1999). Pathogenic sequence variants in the MAN2B1 gene (https://doi.org/10.1007/s10545-018-0175-2) contains supplementary cause a reduction in the activity of lysosomal alpha- material, which is available to authorized users. mannosidase, resulting in impaired glycoprotein degradation in the lysosomes, and ultimately, impaired cellular function * Line Borgwardt and apoptosis (Borgwardt et al 2015; Thomas 2001). AM Line.Gutte.Borgwardt@regionh.dk presents as a multi-systemic disease, characterised by immu- nodeficiency, hearing impairment, facial and skeletal Extended author information available on the last page of the article 1226 J Inherit Metab Dis (2018) 41:1225–1233 abnormalities and mental retardation, among other manifesta- Procedures and treatment tions (Malm and Nilssen, 2008). Other than supportive care, the only treatment option cur- All patients underwent clinical, functional and laboratory as- rently available for AM is allogeneic haematopoietic stem cell sessments at baseline and at pre-specified time points accord- transplantation (HSCT) from a human leukocyte antigens ing to the protocol of their parental trial. Patients enrolled in (HLA)-matched donor, which has a variable outcome and rhLAMAN-07, −09 and − 10 underwent a LO visit at the same carries a serious morbidity and mortality risk (Mynarek et al central location. In the rhLAMAN-10 trial, patients were 2012; Borgwardt et al 2014a). screened for eligibility on day 1 of the visit. Patients who Velmanase alfa is a recombinant human lysosomal alpha- provided informed consent underwent pre-infusion evalua- mannosidase, developed as intravenous (IV) enzyme replace- tions, and were given a single IV infusion of velmanase alfa ment therapy (ERT) for AM (Borgwardt et al 2013). In phase 1 mg/kg on day 2. I/II trials, velmanase alfa was associated with a sustained de- crease in serum oligosaccharides after 18 months of therapy Endpoints (mean percentage change −89.9%, P < 0.001) and achievement of an average improvement of 39 steps in the 3-minute stair Primary endpoints for this analysis were the change from base- climb test (3MSCT; P = 0.004) (Borgwardt et al 2014b). line to LO in serum oligosaccharides, and change from baseline Velmanase alfa treatment was subsequently evaluated in a to LO in the 3MSCT. Serum oligosaccharides were measured phase III placebo-controlled randomised trial (NCT01681953; by high pressure liquid chromatography (HPLC) with ultravio- Borgwardtetal 2017 [submitted]). Here we present long-term let (UV) detection coupled with matrix-assisted laser outcomes in patients with AM treated with velmanase alfa. desorption/ionisation-time of flight (MALDI-TOF) mass spec- trometry. Functional capacity was further assessed using the 6- minute walk test (6MWT), forced vital capacity (FVC % pre- Methods dicted and l, measured by spirometry), and Bruininks- Oseretsky test of motor proficiency (BOT-2). Immunological Study design status was assessed as serum immunoglobulin G (IgG) concen- trations and presence of hypogammaglobulinaemia in patients This study is an integrated analysis of efficacy and safety enrolled in the phase III trial, and classified according to criteria outcomes in patients with AM who participated in velmanase reported in Suppl. Table 2. Level of disability during activities alfa trials and received therapy for up to 4 years in follow-up of daily living and health-related quality of life were assessed clinical trial or compassionate use (CU) programme. using the Childhood Health Assessment Questionnaire (CHAQ) and Euro QOL 5D 5 L (EQ5D5L; used in the phase Analysis population and database generation III trial) surveys, respectively, and results will be presented separately. Treatment-emergent adverse events (TEAEs), ad- Individual patient data from phase I/II (Borgwardt et al 2013) verse drug reactions (ADRs), infusion-related reactions and III trials and the subsequent rhLAMAN-07 (IRRs) and anti-drug antibodies (ADAs) were assessed (NCT01908712), rhLAMAN-09 (NCT01908725) and throughout the trials. rhLAMAN-10 (NCT02478840) studies were integrated into a single database. rhLAMAN-07 and rhLAMAN-09 are on- going clinical trials of once-weekly 1 mg/kg velmanase alfa Statistical analysis treatment in patients from France, or from Poland and Norway, respectively, who previously participated in Baseline data were derived from the original trial in which velmanase alfa trials. rhLAMAN-10 is a single-centre clinical patients were enrolled. LO data were derived from the last trial of 1 mg/kg velmanase alfa in which patients who had non-missing values collected per the protocol of the original previously participated in velmanase alfa clinical trials and trial, or long-term follow-on trial. For patients randomised to subsequently enrolled in the international CU programme placebo in the phase III trial, the baseline for all evaluations were invited to undergo a comprehensive evaluation visit (last was the last non-missing value recorded immediately prior to observation; LO). Inclusion/exclusion criteria are provided in initiation of active treatment after study completion. the Supplementary methods. Integrated analysis data were evaluated in the overall popula- Patients had a confirmed diagnosis of AM, as defined by tion and in age subgroups: adults (aged ≥18 years) and paedi- alpha-mannosidase activity <10% of normal activity, who had atrics (aged <18 years). The absolute changes and percentage participated in the phase I/II and III trials, and were currently changes from baseline to each time point were analysed for all receiving weekly IV infusions of velmanase alfa according to primary and secondary efficacy endpoints, using the paired t- their respective follow-up studies or CU programmes. test and presented with their P-value and 95% CI. J Inherit Metab Dis (2018) 41:1225–1233 1227 Results independent at LO. A statistically significant mean absolute change and percentage change in FVC (percentage predicted) Patients and FVC (L) was observed from baseline to 12 months and to LO. The absolute change in FVC (percentage predicted and L) Thirty-four patients participated in phase I/II and III trials and was greater in paediatric vs adult patients at LO (Table 1 and received velmanase alfa treatment as part of rhLAMAN-07, Fig. 2b in the Supplementary material. The BOT-2 total point −09 or CU programme. Patient disposition is shown in Fig. 1. score for the entire group increased and the percentage change Individual data from 33 patients were included in the integrat- was statistically significant at LO (P = 0.035; Table 1 and ed analysis. Fourteen patients were adult and 19 paediatric at Fig. 2c in the Supplementary material). the time of first infusion. To date, six patients have Results of additional secondary endpoints and PK analyses transitioned from being paediatric to adult patients during their are reported in the Suppl. Tables 2–8. Notably, biomarker treatment period. analysis did not show a significant change in cerebrospinal Baseline demographic and functional characteristics of fluid (CSF) biomarkers from baseline to LO (Suppl. Table 6). each patient are presented in Suppl. Table 1. All patients re- ceived the intended clinical dose of 1 mg/kg/week (equal to Immunological status 25 U used in the phase I/II study; Borgwardt et al 2014b)by IV infusion for ≥12 months, and 19 (57.6%) received the A consistent and significant increase from baseline in mean intended dose for ≥24 months. Mean (standard deviation, serum IgG concentrations was observed at 12 months (n =22 SD) duration of exposure to treatment was 29.3 (15.2) months [data only available for patients initially enrolled in the phase (range: 11.7–53.4 months). The patient population initially III trial], mean percentage change: +47.0% [95% CI: 34.9, enrolled in the phase I/II studies (paediatric population aged 59.1], P < 0.001) and at LO (n = 24; mean percentage change: 6–17 years), received velmanase alfa for up to 48 months +44.1% [95% CI: 32.6, 55.6], P < 0.001), reversing clinically (Fig. 1). Treatment compliance was not assessed in this study, relevant hypogammaglobulinaemia when present. Table 1 but was reported as ≥90% in the phase I/II and III trials. shows the improvements in patients’ serum immunoglobulin status with treatment. Efficacy endpoints A statistically significant clearance of serum oligosaccharides Safety was observed in the overall population from baseline to 12 months (n = 31; mean change: −72.7% [95% CI: –81.4, The incidence of treatment emergent adverse events (TEAEs) −64.1], P < 0.001) and remained statistically significant at LO is summarised in Table 2. MoreADRswerereportedin pae- (n = 33; mean percentage change: −62.8% [95% CI: –74.7, diatric patients, who had generally received more treatments. −50.8], P < 0.001). Similar results were seen across age groups Two patients experienced serious TEAEs that were considered (Fig. 2aand Fig. 1a in the Supplementary material). A signifi- treatment-related: one patient experienced loss of conscious- cant improvement in 3MSCT was also observed at 12 months ness for 2–3 min 8 days after a velmanase alfa infusion; this (n = 31; mean change: +9.3% [95% CI: 2.14, 16.5], P =0.013) event resolved with no action taken regarding the study drug, and this remained significant at LO (n = 33; mean change: and the patient was subsequently diagnosed with epilepsy; the +13.8% [95% CI: 4.61, 22.92], P = 0.004) (Fig. 2b). A greater second patient, who was receiving long-term high-dose ibu- improvement in 3MSCT was observed in paediatric patients, profen therapy (600 mg/day), experienced moderate intensity compared with adults, at both 12 months (n =18; +6.96 acute renal failure that led to temporary discontinuation of steps/min; +15.3%) and LO (n = 19; +10.7 steps/min; +23.1%) study treatment. The renal failure resolved after 92 days. No (Fig. 2b and Fig. 1b in the Supplementary material). Paediatric TEAEs leading to permanent treatment discontinuation were patients with the longest treatment exposure (48 months) expe- reported. rienced a mean absolute increase from baseline of 17.1 steps/ Nineteen IRRs were reported in three patients (9%). min (n = 9, +39.1%) at the end of follow-up. Fourteen of the recorded IRRs occurred in one patient, who A trend towards improved 6MWT was observed at withdrew from the phase I/II and discontinued therapy for 12 months and was statistically significant at LO (Table 1). 21 months, but subsequently enrolled in the phase III study Paediatric patients experienced a greater increase in the and is still receiving treatment. Eight patients (24.2%) devel- 6MWT from baseline to the LO, compared with adult patients oped ADAs at least once during treatment. At least one further (Table 1 and Fig. 2a in the Supplementary material. Four of confirmatory ADA-positive result was present in six of these five paediatric and three of the five adult patients, requiring patients, with ADAs levels around the cut off threshold. Two walking help or aids (defined as cane, walker, crutches or patients had an ADA titre >80 U/ml (maximum values of wheelchair in CHAQ Disability Index) at baseline became 1012 U/ml and 440 U/ml respectively) and experienced IRRs. 1228 J Inherit Metab Dis (2018) 41:1225–1233 Fig. 1 Patient disposition by Phases I and II rhLAMAN-07 parental trial and by trial/CU rhLAMAN-02, -03, -04 N = 7 programme at the time of N = 10 enrolment in rhLAMAN-10 (enrolment in follow-up trial or CU programme determined by 56 national regulations). * Patient 56 participated in rhLAMAN-02 and rhLAMAN-09 rhLAMAN-03, discontinued N = 8 treatment due to an AE but later enrolled in rhLAMAN-05. This Phase III patient is only counted once rhLAMAN-05 ‡ 42 within the integrated analysis. N = 25 Patient 58 participated in the 56 58 rhLAMAN-05 study in the active arm. After completing the Compassionate use programme rhLAMAN-05 study the patient N = 20 received velmanase alfa in the compassionate use programme but did not participate in the rhLAMAN-10 study. Since the rhLAMAN-10 subject received velmanase alfa 67 42 data collection for 12 months in the rhLAMAN- N = 18 05 study, data from this patient are Patient in Phases I and II included in the integrated analysis. Patient 67 participated Patient in Phases I, II and III (active) in the rhLAMAN-05 study in the placebo arm and entered the Patient in Phase III (active) compassionate use programme but did not participate in the 58 did not enroll in rhLAMAN-10 study. As this Patient in Phase III (placebo) rhLAMAN-10 patient did not have any data collected during active treatment, 67 did not enroll he was excluded from the rhLAMAN-10 in rhLAMAN-10 integrated analysis integrated analysis N = 33 56 58 Length of follow-up Trial Patient population Treatment in the rhLAMAN-10 study Phase I Paediatric Active 48 months Phase IIa Paediatric Active 48 months Phase IIb Paediatric Active 48 months Phase III Adult/Paediatric Active vs Placebo 12–36 months Discussion This study is a prospective integrated data analysis of previous clinical trials with different designs (rhLAMAN- In this integrated analysis of the long-term efficacy of 02, −03, −04, −07 and − 09 are open-label, single-arm; velmanase alfa treatment in patients with AM, statistically rhLAMAN-05 is randomised, double-blind, parallel- significant improvements were observed in the co-primary group). The integrated study design was developed to ad- endpoints: serum oligosaccharide levels and 3MSCT. dress the challenges of the rarity of AM and statistical Secondary endpoints evaluating endurance, pulmonary func- analyses of small patient populations. The study protocol tion and motor proficiency also showed improvements up to was written a priori and the statistical analysis plan de- 48 months, which are particularly relevant in the context of a signed before database lock. The reason for choosing this progressively worsening disease. The long-term safety and approach arises from the rarity of the condition and the immunogenicity profile of velmanase alfa appears compatible unusual possibility to be able to collect treatment data for with chronic administration of the drug. up to 4 years before marketing authorisation. N = 34* N = 34 J Inherit Metab Dis (2018) 41:1225–1233 1229 Fig. 2 Changes from baseline in a) Overall Paediatric Adult a) serum oligosaccharides and b) 3MSCT 3MSCT, 3-min stair climb test. -1 -2 -3 −3.68 -4 % change: −4.31 −4.59 –57.6% -5 % change: % change: −5.26 –68.0% −5.41 –62.8% % change: -6 % change: −6.21 –66.6% –72.7% -7 % change: –76.1% -8 Month 12 Last observation b) % change: +23.1% 10.7 % change: % change: +15.3% +13.8% 6.96 6.38 % change: +9.32% 4.25 % change:% change: +1.03% +1.08% 0.49 0.60 Overall Paediatric Adult Month 12 Last observation The presence of a control group limited to the 12-month Performance in functional assessments can be influenced phase III trial (Borgwardt et al 2018) is, at least partially, by developmental stage, understanding of instructions and mitigated by the duration of the follow-up and the repeated willingness to cooperate, all of which can be problematic in assessments. paediatric and/or cognitively disabled patients. These chal- Intra and inter-rater administrative reliability was lenges, combined with the wide age range of study patients maximised by conducting all assessments at one site with (6–35 years), may partially account for inter- and intra-patient standardised administrative guidelines, and the same person- variability. Six patients presented with concomitant condi- nel collected the data on subsequent visits. The results of this tions, such as psychotic behaviour or knee pain, that have analysis clearly support the biochemical efficacy of velmanase compromised their endurance tests. As a severity score is alfa treatment in patients with AM; marked decreases were lacking in alpha-mannosidosis, patients’ disease burden was seen in serum oligosaccharide levels, and statistically sig- evaluated at baseline based on the CHAQ disability index nificant increases in serum immunoglobulins were ob- (DI). The patient population included in the rhLAMAN10 served, with correction of hypogammaglobulinaemia in study scored differently, ranging from severe to mild disabil- many patients. Since the accumulation of mannose-rich ity. A post-hoc analysis revealed how, mean changes from oligosaccharides is considered the causative mechanism baseline to LO showed an improvement in all baseline of cellular dysfunction and hypogammaglobulinaemia in CHAQ-DI score groups in serum oligosaccharides, 3MWT, AM, alongside with oligosaccharide accumulation in lym- 6MWT and percentage of predicted FVC. As of today based phocytes, and is suspected to be the cause of the increase in on the currently available data, no baseline characteristic can rate and severity of infections in AM patients (Malm et al be considered a predictive factor for VA treatment outcome. A 2000), these changes are assumed to produce a therapeutic post-marketing registry study will help in broadening the un- benefit (Malm et al 2014; Muenzer 2014). The decrease in derstanding of the heterogeneity of the alpha-mannosidosis the proportion of patients who hadimpairedorseriously population and the response to treatment. impaired immunoglobulin levels supports the use of serum The 3MSCTwas chosen as an advanced activities-of-daily- immunoglobulin as an additional biomarker of velmanase living measure as it causes greater stress to the musculoskel- alfa activity. All treated patients benefited from an im- etal and cardiorespiratory system, and requires a greater range provement of IgG in serum. of motion and muscle strength, compared with level walking Absolute change (steps/min) Absolute change (µmoI/l) 1230 J Inherit Metab Dis (2018) 41:1225–1233 Table 1 Secondary endpoints results Variable Paediatric Adults Overall NValues Mean (SD) % Mean (SD) NValues Mean (SD) % Mean (SD) NValues Mean (SD) 95% CI % Mean (SD) 95% CI p-value p-value 6MWT (meters) Baseline 19 454.2 (86.3) - 14 483.4 (95.6) - 33 466.6 (90.1) - - - 12-month change 18 35.0 (75.7) 11.4 (29.1) 13 3.8 (43.4) 1.7 (9.8) 31 21.9 (65.2) –2.0, 45.8 7.3 (23.3) –1.2, 15.9 p = 0.071 p = 0.090 Last observation change 19 39.1 (67.6) 11.9 (26.6) 14 0.3 (50.5) 0.7 (11.6) 33 22.4 (63.2) 0.0, 44.8 7.1 (22.0) –0.7, 14.9 p = 0.050 p = 0.071 FVC % of predicted Baseline 17 79.6 (16.4) - 12 92.5 (19.4) - 29 84.9 (18.6) - - - 12-month change 17 6.9 (14.6) 9.7 (19.3) 11 6.0 (9.9) 6.6 (11.7) 30 6.6 (12.8) 1.6, 12.5 8.5 (16.5) 2.1, 14.9 p=0.011 p = 0.011 Last observation change 17 11.6 (15.7) 16.4 (22) 12 3.0 (12.4) 2.1 (16.7) 31 8.1 (14.8) 2.4,13.7 10.5 (20.9) 2.6, 18.5 p = 0.007 p = 0.011 FVC (liters) Baseline 17 2.2 (0.9) - 12 3.2 (1.1) - 29 2.7 (1.1) - - - 12-month change 17 0.5 (0.5) 22.1 (21.9) 11 0.2 (0.3) 7.4 (11.1) 28 0.4 (0.4) 0.27, 0.55 16.3 (19.6) 8.7, 23.9 p < 0.001 p < 0.001 Last observation change 17 0.9 (0.7) 45.9 (39.1) 12 0.2 (0.4) 3.5 (16.3) 28 0.6 (0.7) 0.3, 0.9 28.4 (37.8) 14.0, 42.8 p < 0.001 p < 0.001 BOT-2 Total Score Baseline 19 101.9 (53.8) - 14 113.9 (38.6) - 33 107 (47.6) - - - 12-month change 18 13.6 (17.5) 17.1 (20.6) 13 -0.9 (10.6) 1.6 (13.3) 31 7.5 (16.5) 1.4, 13.5 10.6 (19.3) 3.5, 17.7 p = 0.017 p = 0.005 Last observation change 19 10.7 (29.5) 23 (40.1) 14 -2.5 (9.9) -0.7 (15.9) 33 5.1 (23.9) -3.4, 13.6 13 (33.9) 1.0, 25.0 p = 0.230 p = 0,035 Patients Serum IgG status Baseline (n=24) Month 12 (n=22) Last Observation (n=24) Not/slightly impaired n (%) 15 (62.5) 19 (86.4) 21 (87.5) Impaired n (%) 7 (29.2) 3 (13.6) 3 (12.5) Seriously Impaired n (%) 2 (8.3) 0 (0) 0 (0) 6MWT, 6-Minute Walk Test; BOT-2; Bruininks-Oseretsky Test of Motor Proficiency; FVC, forced vital capacity; SD, standard deviation *“Not/slightly impaired” serum IgG concentration defined relative to Cassidy et al 1974; “impaired” serum IgG concentration defined as 4 mg/mL to lower limit of normal range, “seriously impaired serum IgG concentration defined as < 4 mg/ml J Inherit Metab Dis (2018) 41:1225–1233 1231 Table 2 Summary of TEAEs by age and in the overall population Paediatric Adult Overall n =19 n =14 N =33 Number of Number of patients Number of Number of patients Number of Number of events (%) events (%) events patients (%) Any TEAEs 423 17 (89.5) 123 12 (85.7) 546 29 (87.9) ADRs 69 12 (63.2) 15 5 (35.7) 84 17 (51.5) Serious TEAEs 9 7 (36.8) 5 5 (35.7) 14 12 (36.4) Serious treatment-related 1 1 (5.3) 1 1 (7.1) 2 2 (6.1) TEAEs Severe TEAEs 3 2 (10.5) 1 1 (7.1) 4 3 (9.1) TEAEs with a fatal outcome 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) TEAEs leading to 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) discontinuation ADR adverse drug reaction, TEAEs treatment-emergent adverse events (Nightingale et al 2014). A clear improvement in 3MSCT was pre-symptomatically, to obtain better long-term outcomes evident in the paediatric population, which is notable given (Muenzer 2014; Gabrielli et al 2010;McGillet al 2010; the progressive physical deterioration typically experienced Tylki-Szymanska et al 2012; Tajima et al 2013). by patients with AM and provides evidence supporting the A reduction in serum oligosaccharides and an increase in effect of velmanase alfa treatment. In some patients, improved IgG levels were also achieved in adults. Clinically, these data 3MSCT was also associated with a decreased reliance on are highly relevant when considering the vulnerability of this wheelchair use and other walking help or aids. patient population to infections that can cause significant mor- For many endpoints in this study, the observed improve- bidity. In addition, although the magnitude of the treatment ments were most marked in the paediatric population. To de- effect in domains such as endurance was smaller in adults com- termine whether the 3MSCT improvements in the paediatric pared with paediatric patients, the observed level of improve- population were driven by growth alone, exploratory analyses ment or stabilisation in adults across all domains is still clini- were conducted within the paediatric age groups of <12 years cally important because of the progressive nature of the under- and 12–17 years (representative of age groups characterised in lying disease. Preservation of adequate pulmonary function and healthy children by a slower growth and performance devel- maintenance of endurance and mobility in adult subjects may opment in childhood vs the pubertal growth typical of adoles- lead to a better health-related quality of life than would be cence). Interestingly, mean improvements in 3MSCT were associated with the gradual deterioration typical of AM. similar between the two age groups at LO: +10.6 steps/min Velmanase alfa was generally well tolerated throughout the (+28.5%) in patients <12 years and + 10.7 steps/min (+18.3%) study. A conservative threshold of 1.4 U/ml (lower limit of in patients aged 12–17 years, and thus not proportional to the detection of the assay) was set with regard to detecting ADAs. improvement rate expected by growth alone. A limited number of patients developed ADAs, with no clear The positive results for the 6MWT are consistent with the effect on the co-primary efficacy outcomes (see also results from the 3MSCT and also suggest a mobility benefit Borgwardt et al 2017), despite for one of the two patients with associated with velmanase alfa treatment. A greater increase ADA > 80 U/ml who presented oligosaccharides above base- in FVC (% predicted) observed in the paediatric is also notable line levels at LO. Three patients experienced IRRs, all of given the poorer pulmonary function at baseline in paediatric which were mild or moderate in intensity and which resolved patients (mean FVC [%] at baseline 79.6% vs 92.5% in pae- either spontaneously or with medical management. Of note, diatric and adult patients, respectively). The comparative im- two of these patients had high levels of ADAs (>80 U/ml). A provements in motor and pulmonary function in those who clear correlation between ADA and IRR occurrence has never start treatment as paediatric patients, compared with those been established in other therapies. Interestingly, the two who begin treatment as adults, suggest that patients may ben- patients with highest titres of ADA in VA clinical develop- efit more from treatment started early in the disease course. ment programme developed IRR, suggesting the impor- This observation is in line with previous studies of long-term tance of keeping ADA monitoring in the future. The lim- outcomes of patients receiving IV ERT for lysosomal storage ited number of patients with high titre of ADA does not disorders, and supports that treatment of patients with such allow driving conclusions for today and the future registry disorders is recommended and should start early, preferably study will help in providing new insights. The data were 1232 J Inherit Metab Dis (2018) 41:1225–1233 consent was obtained from the patient or his/her legally authorised guard- collected longitudinally, and form the largest clinical ian(s) prior to performing any trial-related activities. dataset evaluating ERT in AM to date. Our findings sug- The study was conducted with the Good Clinical Practice guidelines, gest that the significant improvements in biochemical and and following all other requirements of local laws. functional efficacy measures associated with velmanase alfamaypersist forupto4yearsinpaediatricpatients, Open Access This article is distributed under the terms of the Creative with adult patients experiencing significant improvements Commons Attribution 4.0 International License (http:// in serum oligosaccharide levels and stabilisation of func- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give tional performance up to 2 years after treatment initiation. appropriate credit to the original author(s) and the source, provide a link The long-term safety outcomes suggest that there are no to the Creative Commons license, and indicate if changes were made. additional risks associated with extended treatment. The lack of effect on CSF biomarkers is an area of unmet need and a future research focus. References Acknowledgements BOT-2 analyses were interpreted by Dr. Dawn Borgwardt L, Dali CI, Fogh J et al (2013) Enzyme replacement therapy Phillips. The velmanase alfa study team would like to acknowledge the for alpha-mannosidosis: 12 months follow-up of a single Centre, patients involved in this project, all the “ALPHAMAN” members, includ- randomised, multiple dose study. J Inherit Metab Dis 36:1015–1024 ing the extensive and fundamental contribution of Prof. Dag Malm in the Borgwardt L, Lund AM, Dali CI (2014a) Alpha-mannosidosis - a review field of research in alpha-mannosidosis. of genetic, clinical findings and options of treatment. Pediatr Endocrinol Rev 12:185–191 Funding rhLAMAN-02, −03, −04 and − 05 were conducted under and Borgwardt L, Dali CI, Fogh J (2014b) Enzyme replacement therapy in co-funded by the EU FP7 project ALPHA-MAN [FP7-HEALTH- children and adolescents with α-mannosidosis: an 18-month follow- 2010-261331]. rhLAMAN-07 and -09 were previously sponsored up. J Inborn Errors Metab Screen 2: Abstract #1180 by Zymenex and are currently sponsored by Chiesi Farmaceutici S.p.A. Zymenex sponsored rhLAMAN-10 and the corresponding Borgwardt L, Stensland HM, Olsen KJ et al (2015) Alpha-mannosidosis: integrated patient analysis was reported by Chiesi. The sponsor pro- correlation between phenotype, genotype and mutant MAN2B1 vided study drug, and was involved in the study design, protocol subcellular localisation. Orphanet J Rare Dis 10:70 development, regulatory and ethics approvals, safety monitoring and Borgwardt L, Guffon N, Amraoui Y et al (2018) Efficacy and safety of reporting, data management and data analysis and interpretation. velmanase alfa in the treatment of patients with alpha-mannosidosis: The lead authors/corresponding author (AML and LB) were directly results from the core and extension phase analysis of a phase III involved in the design of the trial, had full access to all the data and multicentre, double-blind, randomised, placebo-controlled trial. had final responsibility for development of the manuscript and sub- [submitted for parallel publication in JIMD]. https://doi.org/10. mission for publication. Chiesi Farmaceutici S.p.A. funded third- 1007/s10545-018-0185-0 party writing assistance, provided by Health Interactions. Cassidy JT, Nordby GL, Dodge HJ (1974) Biologic variation of human serum immunoglobulin concentrations: sex-age specific effects. J Chron Dis 27:507–516 Compliance with ethical standards Gabrielli O, Clarke LA, Bruni S, Coppa GV (2010) Enzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS Competing interests AML, LB, NG, MGC, LDM, BH, SAJ were in- I: 5-year follow-up. Pediatrics 125:e183–e187 vestigators in at least one of the rhLAMAN-02, −03, −04 and − 05 studies Malm D, Nilssen Ø (2008) Alpha-mannosidosis. Orphanet J Rare Dis 3:21 that were sponsored by Zymenex and part of the ALPHA-MAN project Malm D, Halvorsen DS, Tranebjaerg L, Sjursen H (2000) funded by the EU. AML and NG have received investigator’s fees from Immunodeficiency in alpha-mannosidosis: a matched case-control Zymenex and Chiesi as Principal Investigators in the rhLAMAN-07 or − study on immunoglobulins, complement factors, receptor density, 09 studies. DP has received consultancy fees from Chiesi. DC has re- phagocytosis and intracellular killing in leucocytes. Eur J Pediatr ceived research funds, consultancy fees and speaker honoraria from 159:699–703 Sanofi-Genzyme, research and service support funding, and funding for Malm D, Riise Stensland HM, Edvardsen Ø, Nilssen Ø (2014) The nat- travel and meeting expenses from Shire, and funding for travel and meet- ural course and complications of alpha-mannosidosis–a retrospec- ing expenses from Biomarin. PH reports consulting fees from BioMarin, tive and descriptive study. J Inherit Metab Dis 37:79–82 Inventiva, Armagen, PTC and REGENXBIO, and consulting fees, travel McGill JJ, Inwood AC, Coman DJ et al (2010) Enzyme replacement and honoraria from Chiesi, Shire, Sanofi-Genzyme and Alexion. DA, FC, therapy for mucopolysaccharidosis VI from 8 weeks of age–asib- SG are employees of Chiesi Farmaceutici S.p.A. JF is an employee and ling control study. Clin Genet 77:492–498 board member of Zymenex A/S. SAJ has received consulting fees from Meikle PJ, Hopwood JJ, Clague AE, Carey WE (1999) Prevalence of Genzyme, Shire, Biomarin, Alexion, Ultragenyx and Orchard lysosomal storage disorders. JAMA 281:249–254 Therapeutics. YA has received consulting fee from Chiesi Farmaceutici Meikle PJ, Ranieri E, Simonsen H et al (2004) Newborn screening for S.p.A. LB has received travel reimbursement from Chiesi for participa- lysosomal storage disorders: clinical evaluation of a two-tier strate- tion in two congresses when presenting the study data. C. Laroche, P. gy. Pediatrics 114:909–916 Dolhem, A. Tylki-Szymanska, M. Lopez-Rodriguez, E. Guillén-Navarro, Muenzer J (2014) Early initiation of enzyme replacement therapy for the C. I. Dali, N. Muschol, B. Héron, and J. M. H. Van den declare that they mucopolysaccharidoses. Mol Genet Metab 111:63–72 have no conflict of interest. Mynarek M, Tolar J, Albert MH et al (2012) Allogeneic hematopoietic Ethical approval and patient consent statement All procedures follow- SCT for alpha-mannosidosis: an analysis of 17 patients. Bone ed were in accordance with the ethical standards of the responsible com- Marrow Transplant 47:352–359 mittee on human experimentation (institutional and national) and with the Nightingale EJ, Pourkazemi F, Hiller CE (2014) Systematic review of Helsinki Declaration of 1975, as revised in 2000 (5). Written informed timed stair tests. J Rehabil Res Dev 51:335–350 J Inherit Metab Dis (2018) 41:1225–1233 1233 Tajima G, Sakura N, Kosuga M, Okuyama T, Kobayashi M (2013) Tylki-Szymanska A, Jurecka A, Zuber Z, Rozdzynska A, Marucha J, Czartoryska B (2012) Enzyme replacement therapy for Effects of idursulfase enzyme replacement therapy for mucopolysaccharidosis type II when started in early infancy: com- mucopolysaccharidosis II from 3 months of age: a 3-year follow- parison in two siblings. Mol Genet Metab 108:172–177 up. Acta Paediatr 101:e42–e47 Thomas GH (2001) Disorder of glycoprotein degradation. The metabolic University of Tromsø and the University Hospital of North Norway. & molecular bases of inherited disease. McGraw-Hill, New York, p Alpha-mannosidosis Mutation Database. https://apex.jupiter.no/ 2001 apex/f?p=101:1. Accessed15June2017 Affiliations 1,2 1,2,3 4 4 4 5 Allan M. Lund & Line Borgwardt & Federica Cattaneo & Diego Ardigò & Silvia Geraci & Mercedes Gil-Campos & 6 7 8 9 10 Linda De Meirleir & Cécile Laroche & Philippe Dolhem & Duncan Cole & Anna Tylki-Szymanska & 11 12 1 13 14 Monica Lopez-Rodriguez & Encarna Guillén-Navarro & Christine I. Dali & Bénédicte Héron & Jens Fogh & 15 16 17 18 19 Nicole Muschol & Dawn Phillips & J. M. Hannerieke Van den Hout & Simon A. Jones & Yasmina Amraoui & 20 21 Paul Harmatz & Nathalie Guffon 1 12 Departments of Paediatrics and Adolescent Medicine, Centre Medical Genetics Section, Hospital Clínico Universitario Virgen for Inherited Metabolic Diseases, Copenhagen, Denmark de la Arrixaca, IMIB-Arrixaca, CIBERER-ISCIII, Madrid, Spain 2 13 Department of Clinical Genetics, Centre for Inherited Metabolic Service de Neuropédiatrie, Centre de Référence des Maladies Diseases, Copenhagen University Hospital, Rigshospitalet, Lysosomales, and Sorbonne Université, GRC n°19, pathologies Copenhagen, Denmark Congénitales du Cervelet-LeucoDystrophies, AP-HP, Hôpital Armand Trousseau, F-75012 Paris, France Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Zymenex A/S, Hillerød, Denmark 4 15 Chiesi Farmaceutici S.p.A, Parma, Italy International Center for Lysosomal Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Unidad de Metabolismo e Investigación Pediátrica, Hospital Universitario Reina Sofía, IMIBIC, Universidad de Córdoba, Evidera, Bethesda, MD, USA CIBERObn, Córdoba, Spain Center for Lysosomal and Metabolic Diseases (department of Paediatric Neurology and Metabolism, Universitair Ziekenhuis, Pediatrics), Erasmus MC University Medical Center – Sophia Brussels, Belgium Children’s Hospital, Rotterdam, The Netherlands 7 18 Limoges Hospital, Limoges, France Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Centre Hospitalier de Saint-Quentin, Saint-Quentin, France Center for Pediatric and Adolescent Medicine, Villa Department of Medical Biochemistry and Immunology, Metabolica, University Medical Center Mainz, Mainz, Germany University Hospital of Wales, Cardiff, Wales, UK UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA Department of Paediatric, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, Warsaw, Poland Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, Lyon, France Hospital Central Cruz Roja, Madrid, Spain
Journal of Inherited Metabolic Disease – Springer Journals
Published: May 3, 2018
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