Oral treatment with miglustat for 24 months prevented pathological storage in liver as evidenced by the maintenance of liver size. The mean percent change in liver volume from baseline during 24 months of miglustat therapy (−1.1) was well within the pre-defined non-inferiority limit of 10%, and thus the primary efficacy endpoint of this 24-month, open-label non-inferiority study was met. In addition, all patients who were within the proposed therapeutic goal for liver volume at baseline were maintained within this goal throughout the study [21
]. Liver volume was therefore maintained in patients with stable type 1 Gaucher disease who changed to miglustat after previous long-term enzyme therapy.
Change in liver volume has been recommended as a consistent clinical indicator of disease course and treatment effects in type 1 Gaucher disease as it does not tend to show the degree of inter-patient variability seen with other key disease parameters [28
]. Liver volume or ratio has been assessed as the primary efficacy endpoint in a number of previous clinical trials alone or in combination with spleen volume [15
], and was chosen following detailed discussions with the EMA at the time of trial design. Moreover, the analytical approach adopted in this study allowed an objective, quantitative assessment of this endpoint.
Inclusion of a placebo arm was considered unethical and impracticable in this treatment and patient setting, which is unfortunate as the absence of a suitable control group prevents a robust evaluation of the effects of miglustat in patients who have already had the benefit of enzyme therapy. Previous data indicate that a 2-year treatment interruption would carry a risk of recurrent clinical disease in some patients, accompanied by severe fatigue and reappearance of bone pain and other skeletal manifestations of untreated Gaucher disease [10
Exploratory analysis of the key secondary efficacy endpoints (spleen volume, hemoglobin concentration and platelet count) were included in the trial design after the primary endpoint was agreed with the EMA, based on their scientific relevance. Overall, these secondary endpoints indicated stable disease between baseline and the end of miglustat treatment. High proportions of patients who were within therapeutic goals for each parameter at baseline were maintained within goal up to Month 24.
The clinical relevance of the absolute mean changes in secondary efficacy parameters, most of them in the direction of disease progression, is difficult to interpret. The mild baseline disease burden of the study population should be taken into account. For instance, the 102 mL increase in spleen volume in non-splenectomized patients at end of treatment should be considered in the context of the low mean absolute baseline value of 510 mL, compared with values normally seen in long-term enzyme therapy patients. In all, 8/30 (27%) patients showed clinically relevant increases in spleen volume.
Small mean absolute reductions in hemoglobin were observed during miglustat therapy(−0.95 g/dL from a baseline of 14.8 g/dL). Four out of 41 (10%) patients had clinically relevant decreases in hemoglobin indicative of disease progression but, as with the organ volume findings, the great majority (94%) of patients was maintained within the normal range. The proportion of patients remaining stable for platelet count (85%) from baseline to Month 24 was slightly lower than for other key parameters, with an absolute mean change of −44.1
/L. Nine of 41 (22%) patients had decreased platelet counts that were considered potentially relevant.
The relevance of plasma chitotriosidase for monitoring disease status in patients with stable, mild type 1 Gaucher disease after switching to miglustat in relation to prognosis is currently unclear. Consistent with other systemic disease parameters, the median absolute chitotriosidase activity was low at baseline (963 nmoles/[mL*hr]) but was variable between patients despite long-term enzyme therapy. Changes in chitotriosidase activity in response to miglustat treatment were also highly variable, with some patients showing marked increases; this suggests that these patients had ‘subclinical’ disease progression, which was unassociated with clinical events. Miglustat has been shown to significantly reduce plasma chitotriosidase activity in treatment-naïve patients over 3 years of therapy [13
]. In the previous open-label randomized study reported by Elstein et al. [19
], mean chitotriosidase activity remained stable during miglustat therapy in 27/28 (96%) patients with type 1 Gaucher disease after switching from long-term enzyme therapy. Similar findings were reported in the Spanish ZAGAL cohort study [16
Bone pain (rated on a visual analogue scale ranging from 0 to 100) was unchanged during 24 months of miglustat treatment, and none of the 17 evaluable patients who were free of bone pain at baseline experienced pain episodes throughout follow up. MRI-based BMB scores indicated a slight increase in bone marrow infiltration over 24 months. Again, this may indicate subclinical disease progression in some patients. Of note, there was no median change in BMB score among the six splenectomized patients, compared with the small median change (+3) among the 15 patients with intact spleens. Previously, stable BMB scores have been observed for up to 18 months in patients changed from enzyme therapy to miglustat [34
]. Long-term follow up in a Spanish cohort of switch patients showed an improvement in lumbar spine bone marrow infiltration during 48 months of therapy [16
It is not possible to discern whether patient genotype had an influence on the changes in these disease parameters, due to the small sample size. From the genotype data presented in Table there does not appear to be any clear association of a particular genotype with disease worsening or improvement during miglustat therapy.
To ensure the safety of patients who might show deterioration, we used conservative exploratory criteria to identify patients with ‘suspected disease worsening’ after switching from a stable dose of enzyme therapy to miglustat. These criteria do not reflect those generally used in clinical practice [35
]. Based on the criteria defined in the trial protocol, miglustat treatment was discontinued in a total of six patients, as adjudicated by the Steering Committee. The number of patients finally adjudicated as exhibiting disease worsening (n = 13) was lower than the total number of cases with suspected disease worsening referred by investigators during or at the end of the study (n = 20). This may be related to the fact that decision making regarding disease worsening during the study was based on local readings, while the Steering Committee utilized both local readings and standardized central readings at the end of the study.
No new or unexpected safety findings came to light during this 24-month study and, overall, the safety and tolerability of miglustat was found to be consistent with its known safety profile [11
]. Gastrointestinal effects such as diarrhea and flatulence were the most frequently reported adverse events, and were the most frequent reason for premature discontinuation of therapy. In this respect, it is regrettable that firm guidance for avoiding or ameliorating gastrointestinal disturbances, such as dietary modification in the early phase of treatment, was not specified in the study protocol. Such interventions during the initial weeks of miglustat therapy can substantially improve tolerability [37
]. Notably, patients attending the one center where individual dietary guidance was
provided reported the least severe gastrointestinal side effects.
No new cases of peripheral neuropathy with clinical symptoms attributable to miglustat occurred in the present study. The observed 11.9% prevalence of neuropathy at baseline is in agreement with the prevalence of peripheral neuropathy (11%) reported in a previous study of 103 type 1 Gaucher disease patients not receiving this agent [4
]. Findings from the neuropsychological assessments conducted in this study were in line with data from the miglustat post-marketing surveillance program [36
To an extent, the current study allows a limited interpretation of the therapeutic role of miglustat in Gaucher disease. The wide variability in response between patients included in this study, alongside the appreciable rate of premature discontinuations from therapy, suggest that the use of miglustat as a maintenance therapy in GD1 might be suitable for a distinct group of patients. However, additional data would be required to fully define such a group.
With regard to the higher than expected patient dropout from this study, it seems likely that the stringent criteria we adopted to define ‘disease worsening’ may have contributed to their withdrawal. However, we defend the rigorous adjudication process because of the need to ensure that no patient experienced unnecessary or untoward deterioration during the protracted (2-year) course of the trial. The criteria that were adopted for withdrawing patients from this study do not reflect those that are used in therapeutic decision-making regarding treatment failure in clinical practice. Finally, while an examination of the achievement of therapeutic goals was included in the statistical analysis plan, it was not defined a priori, and thus should be interpreted with caution. In addition, such an analysis may lack sensitivity, as it is possible that patients experiencing deterioration in a particular disease parameter could still remain within the range for the goal.