Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9‐month, global, randomized, double‐blind, non‐inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment‐naïve patients aged 3–73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent‐to‐treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per‐protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent‐to‐treat and per‐protocol populations, respectively. The lower bound of the 97.5% one‐sided confidence interval in both populations lay within the pre‐defined non‐inferiority margin of ?1.0 g/dL, confirming that velaglucerase alfa is non‐inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross‐reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed. Am. J. Hematol. 88:179–184, 2013. © 2012 Wiley Periodicals, Inc.     

Epileptic seizures in non-ketotic hyperglycemia]

Seizures are common in hyperglycemia and are often the first manifestation particularly in non-ketotic hyperglycemia (NKH). Published reports emphasize partial motor seizures almost exclusively. Here we present the clinical, biological and electrophysiological features of 22 consecutive patients with NKH who developed focal seizures and were treated in our department. Neurological exam was normal in 15 cases. When abnormal, it showed postictal obnubilation or diabetic polyneuropathy. Interictal EEG (obtained in 17 patients) showed focal or generalised slowing in 65% of cases, and ictal EEG (six patients) showed rapid spikes most often unilateral. CTs were normal in 77% of cases, and showed age-compatible cortico-subcortical atrophy in the others. All patients were alert, with glucose values between 13.6 and 55 mmoles/l and osmolarity values increased in all cases to a mild or moderate extent (266-309.20 mosm/l). Three out of 22 patients (14%) presented with motor epilepsy partialis continua. In 11/22 cases (50%), diabetes mellitus had not been diagnosed previously. Seizures associated with NKH were resistant to anticonvulsant treatment but responded well to insulin therapy and rehydration. They subsided completely in an average of 4 days, and only one patient had to be transiently transferred to ICU. We conclude on the importance of an early diagnosis of this condition to prevent malignant evolution of the epileptic syndrome into a state of hyperosmolarity and coma associated with a much higher mortality.     

Fuel chip-induced hypersensitivity pneumonitis caused by penicillium species

Two cases of Penicillium-induced hypersensitivity pneumonitis in farmers handling fuel chips are presented. Attention should be paid to safe handling of all types of solid fuel (wood, chips, and peat) and other materials in which mold may grow.     

Induction of gastric cancer in monkeys by N-methyl-N-nitro-N-nitrosoguanidine (MNNG)

N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was administered to 9 Macaca fascicularis monkeys (7 males and 2 females) through a tube at a dose of 40 mg/kg body weight 3 times a month. Tumors of the pyloric part of the stomach were observed in 2 male monkeys after MNNG doses of 800 and 848 mg/kg body weight, with a latent period of tumor development of 49 and 50 weeks, respectively. Histologically, in one case the tumor was a solid carcinoma, and in the other it had a mixed structure showing alternating solid and signet ring cell carcinoma areas.     

Outcomes after 18 months of eliglustat therapy in treatment‐naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial

Eliglustat, an oral substrate reduction therapy, is a first‐line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18‐month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double‐blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double‐blind period, eliglustat treatment during the 9‐month, open‐label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double‐blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment‐naïve patients. Eliglustat was well‐tolerated, and there were no new safety concerns with longer‐term exposure.