Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports.

BACKGROUND: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. CASE PRESENTATION: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy. CONCLUSION: While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy and enzyme replacement therapy, the current case reports demonstrate that judicious use of combination therapy may be of benefit in some cases.

Taliglucerase alfa: an enzyme replacement therapy using plant cell expression technology.

Gaucher disease (GD) is a rare, genetic lysosomal storage disorder caused by functional defects of acid ß-glucosidase that results in multiple organ dysfunction. Glycosylation of recombinant acid human ß-glucosidase and exposure of terminal mannose residues are critical to the success of enzyme replacement therapy (ERT) for the treatment of visceral and hematologic manifestations in GD. Three commercially available ERT products for treatment of GD type 1 (GD1) include imiglucerase, velaglucerase alfa, and taliglucerase alfa. Imiglucerase and velaglucerase alfa are produced in different mammalian cell systems and require production glycosylation modifications to expose terminal α-mannose residues, which are needed for mannose receptor-mediated uptake by target macrophages. Such modifications add to production costs. Taliglucerase alfa is a plant cell-expressed acid ß-glucosidase approved in the United States and other countries for ERT in adults with GD1. A plant-based expression system, using carrot root cell cultures, was developed for production of taliglucerase alfa and does not require additional processing for postproduction glycosidic modifications. Clinical trials have demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in adult, ERT-naïve patients with symptomatic GD1, and for such patients previously treated with imiglucerase. These included significant improvements in organomegaly and hematologic parameters as early as 6months, and maintenance of achieved therapeutic values in previously treated patients. Ongoing clinical trials will further characterize the long-term efficacy and safety of taliglucerase alfa in more diverse patient populations, and may help to guide clinical decisions for achieving optimal outcomes for patients with GD1.

The pathophysiology of GD - current understanding and rationale for existing and emerging therapeutic approaches.

Gaucher disease is a genetic disorder of sphingolipid metabolism resulting from dysfunction of the lysosomal membrane-associated glycoprotein glucocerebrosidase (GBA) and resulting in intracellular accumulation of glucosylceramide and other glycolipids. Although the gene defect and relevant biochemical pathways have been defined, the mechanisms by which substrate accumulation causes disease manifestations are not well understood. The direct effects of a build up of substrate laden cells may account for some aspects of disease but the overall pathology is likely to be more complex with effects of stored material on a variety of intra and extra cellular functions. In this article we review the GBA gene and its protein product, with associated defects, lipid metabolism and storage, enzyme misfolding and endoplasmic reticulum stress, calcium homeostasis, oxidative stress and autophagy and at each point examine how therapies that are currently available, in clinical development or at earlier stages of basic research might address the pathological mechanisms.

Splenic nodules in paediatric Gaucher disease treated by enzyme replacement therapy.

BACKGROUND: The natural history of focal splenic lesions in paediatric Gaucher disease (GD) is unknown and these lesions are thought to persist despite enzyme replacement therapy (ERT). OBJECTIVE: To assess the prevalence, evolution and resolution of splenic nodules in a cohort of paediatric Gaucher patients treated with ERT. MATERIALS AND METHODS: The US findings in 37 children with GD were retrospectively reviewed. A total of 28 children underwent serial abdominal US examinations as part of their initial assessment and during routine follow-up. All patients received ERT. RESULTS: Six children (21%) had splenic nodules on US examination, either at presentation or on follow-up examination. In all six patients, the nodules had resolved on follow-up imaging, with resolution taking 17 months to 4 years 8 months. Two sets of siblings developed nodules that resolved over a similar time period. CONCLUSION: Disappearance of focal splenic lesions in children with GD during follow-up has not been previously reported. The development of new focal splenic lesions in children with GD whilst on ERT has not been previously documented.

The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy.

Enzyme replacement therapy is now well established as the treatment of choice in Type I Gaucher disease. Historically higher dosage regimens have been used in preference to lower doses despite the little clinical evidence in the way of large controlled clinical trials to support this. Moreover, the extraordinary cost of therapy means that not all eligible patients are able to be treated at the higher dose. Twelve type I adult patients with relatively severe disease were commenced on a very low dose of 7.5U of alglucerase/imiglucerase per kg every two weeks (initially given thrice weekly and later weekly). Follow-up 5 year data reveal a good visceral and haematological response with outcomes consistent with recently published treatment guidelines. Satisfactory clinical and radiological skeletal improvement was also demonstrated in most patients. Three patients had an inadequate overall skeletal response to therapy. Biomarkers also steadily improved although perhaps not quite at the same rate as that seen in higher doses. Very low dose enzyme replacement therapy may be appropriate for adult type I Gaucher patients with mild-moderate skeletal disease.

Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement.

Enzyme replacement therapy (ERT) with imiglucerase reduces hepatosplenomegaly and improves hematologic parameters in Gaucher disease type 1 within 6-24 months. Miglustat reduces organomegaly, improves hematologic parameters, and reverses bone marrow infiltration. This trial evaluates miglustat in patients clinically stable on ERT. Tolerability of miglustat and imiglucerase, alone and in combination, pharmacokinetic profile, organ reduction, and chitotriosidase activity were assessed. Thirty-six patients stable on imiglucerase were randomized into this phase II, open-label trial. Statistically significant changes from baseline were assessed (paired t test) on primary objectives with secondary analyses on biochemical and safety parameters. Liver and spleen volume were unchanged in switched patients. No significant differences were seen between groups regarding mean change in hemoglobin. Mean change in platelet counts was only significant between miglustat and imiglucerase groups (P = .035). Chitotriosidase activity remained stable. In trial extension, clinical endpoints were generally maintained. Miglustat was well tolerated alone or in combination. Miglustat's safety profile was consistent with previous trials; moreover, no new cases of peripheral neuropathy were observed. Gaucher disease type 1 (GD1) parameters were stable in most switched patients. Combination therapy did not show benefit. Findings suggest miglustat could be an effective maintenance therapy in stabilized patients with GD1.

[Osteoarticular manifestations of Gaucher disease in adults: pathophysiology and treatment]. / Atteintes ostéoarticulaires de la maladie de Gaucher chez l'adulte: de la physiopathologie au traitement.

Gaucher disease frequently has severe osteoarticular manifestations that may be disabling. Ischemic phenomena cause the most serious complications and lead to irreversible lesions. Aseptic osteonecrosis of the hip is the most disabling complication; it causes intense early bone pain and often joint collapse and secondary osteoarthritis in young adults. Localized or systemic bone fragility explains osteopenia, osteoporosis, and fractures (vertebral collapse with irreversible kyphosis causing chronic morbidity). Although no double-blind randomized studies have assessed the bone effects of enzyme replacement therapy, it has been shown effective in reducing bone pain in about half of all treatment-naive patients within 1 to 2 years and in improving bone mineral density after 3 years. In open-label trials, substrate reduction therapy (miglustat) reduced both bone pain and bone marrow infiltration. Specific treatment for bone fragility, with bisphosphonates for example, should be considered after rigorous individualized evaluation and assessment of other risk factors.

[Therapeutic objectives in Gaucher disease]. / Buts thérapeutiques dans la maladie de Gaucher.

Evidence-based therapeutic goals have been developed by European and North American experts in the field of Gaucher disease (GD, lysosomal acid beta glucosidase deficiency, OMIM 230 800) in an attempt to reverse the entire disease phenotype, improve quality of life and prevent life-threatening complications. Patients with GD usually have maximal clinical benefit when enzyme replacement treatment (ERT) efficiency is administered at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, imiglucerase is the standard of care for type 1 GD due to its high efficiency at improving bleeding tendencies, anemia, reversing heptosplenomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99%. Treatment of GD is a lifelong treatment that patients should not interrupt without a careful monitoring of the disease evolution.

[Clinical study of the French cohort of Gaucher disease patients]. / Etude clinique de la cohorte française de patients atteints de la maladie de Gaucher.

A census is currently being carried out of the French cohort of Gaucher disease patients. This article describes its preliminary results, obtained by analysing the records of 101 patients for whom clinical and laboratory data were accessible while they were receiving enzyme therapy. At the time of diagnosis, all patients presented with splenomegaly, 70% had asthenia and one in three was already affected by major bone damage. After 1 year of enzyme therapy, splenomegaly had diminished by half and the different scores (asthenia, bone pain and abdominal pain, etc.) had markedly improved, as had the biochemical markers. As for the 6 patients affected by type 3 Gaucher disease and treated with enzyme therapy after the onset of neurological signs, a stabilisation or even some improvement of the disease was observed. In-depth study of the French cohort should make it possible to formulate consensus recommendations for the future, based on well-established data.

Therapeutic goals in Gaucher disease.

Evidence-based therapeutic goals have been developed by several European and American experts in Gaucher disease in order to attempt to reverse the entire Type 1 Gaucher phenotype, prevent complications, improve quality of life and prevent life-threatening complications. Patients with Gaucher disease will benefit by maximum enzyme replacement treatment (ERT) efficiency if it is given at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, Cerezyme is the standard of care for all severities of type 1 Gaucher disease due to its high efficiency at ameliorating bleeding tendencies, reversing organomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99%. Treatment of Gaucher disease is a long-life treatment that the patient should not interrupt without a careful monitoring of the disease evolution.

Miglustat: new drug. In type 1 Gaucher's disease : a slight benefit after imiglucerase therapy.

(1) For patients with type 1 Gaucher's disease the standard treatment is imiglucerase enzyme replacement therapy, provided in fortnightly intravenous infusions. (2) Miglustat inhibits the synthesis of glucosyl-ceramide, the cerebroside that accumulates in Gaucher's disease. Miglustat is now licensed for oral therapy in patients with mild to moderate type 1 Gaucher's disease and who cannot take imiglucerase, regardless of the reason. (3) The evaluation data we managed to gather (see literature search) includes data from three trials involving a total of 82 patients. One of these trials compared miglustat with ongoing imiglucerase therapy. Miglustat slightly reduced the size of the liver and spleen, and slightly increased the haemoglobin level and platelet count after 18 months. The impact of these effects is unknown, especially on bone disorders. In patients with previous response to imiglucerase, miglustat has not been found to maintain clinical effects in the longer term. (4) Miglustat has many adverse effects, some of which occur very frequently, such as diarrhea (86%), weight loss (64%), peripheral neuropathies (19%), tremor (29%), and cognitive disorders. Animal studies suggest a risk of reproductive toxicity. (5) In practice, miglustat therapy offers minimal benefits for the few patients who cannot use imiglucerase. The potential advantages of miglustat therapy relative to purely symptomatic treatment must be carefully weighed in individual patients.

Decreased bone density in splenectomized Gaucher patients receiving enzyme replacement therapy.

Little is known about the effect of enzyme replacement therapy (ERT) on the bone abnormalities in Gaucher disease. Splenectomized Gaucher patients tend to suffer the most severe skeletal complications. We hypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infusions to increase bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomized Gaucher patients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxyvitamin D3; 0.25-3.0 microg/day) alone for the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during months 7-12; Group 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1-6; and Group 3, enzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after the first 6 months of therapy. The primary outcome measure was bone mineral density of the lumbar spine measured by single-energy quantitative CT. Bone density by single-energy CT (P = 0.001) and by dual-energy CT (P = 0.06) declined overall, but there was no significant difference between the groups. Calcitriol had no significant effect on bone density. Fat fraction in lumbar spine increased (P = 0.000) and skeletal MRI scores improved. Bone-specific alkaline phosphatase (P = 0.002) and serum osteocalcin increased (P = 0.008), while blood cyclic AMP and urinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume significantly improved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone composition in splenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an inadequate marker of clinical efficacy for treating skeletal involvement in Gaucher disease.