Long‐term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment‐naïve patients with Gaucher disease

Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell–expressed recombinant therapeutic protein. Herein, we report long‐term safety and efficacy results of taliglucerase alfa in treatment‐naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment‐related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36‐month results of taliglucerase alfa in treatment‐naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656–660, 2016. © 2016 Wiley Periodicals, Inc.     

Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase

Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT‐1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open‐label, 12‐month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9–71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment‐related: a Grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE‐related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa Phase 3 clinical trial program. Am. J. Hematol. 88:172–178, 2013. © 2012 Wiley Periodicals, Inc.     

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease

Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long‐term disease‐specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty‐eight of 40 patients (aged 9–71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12‐month, open‐label clinical study, and for 10–50 months in an extension study. The most common adverse events (AEs) judged to be drug‐related in the extension were fatigue and bone pain. No drug‐related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 × 10⁹/L at baseline, were given at least one 15 U/kg‐dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for anti‐imiglucerase antibodies at baseline. This patient tested positive for anti‐velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes. Am. J. Hematol. 90:592–597, 2015. © 2015 Wiley Periodicals, Inc.     

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.     

Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease

IntroductionTherapeutic goals have been described to monitor achievement, maintenance and continuity of therapeutic response in patients with type 1 Gaucher disease receiving enzyme replacement therapy.AimTo benchmark the impact of velaglucerase alfa treatment against therapeutic goals for 5 key clinical parameters of type 1 Gaucher disease (anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology).MethodsIn an open-label Phase I/II study, twelve adults with symptomatic type 1 Gaucher disease and intact spleens received velaglucerase alfa for 9 months (60 U/kg infusion every other week [EOW]). Eleven patients completed the study and 10 enrolled in a long-term extension. After 1 year, patients who achieved ≥ 2 hematological or organ goals began step-wise dose reduction from 60 to 45 then 30 U/kg EOW. Data for anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology at baseline and 4 years are available for 8 patients (3 male, 5 female). The proportion of patients at goal for anemia, thrombocytopenia, hepatomegaly and splenomegaly at baseline was compared with the proportion achieving each goal at 4 years. The proportion achieving the skeletal pathology goal was determined on the basis of Z-score improvement from baseline to 4 years. The proportion of patients who achieved all 5 goals at 4 years was compared with the proportion at goal for all 5 parameters at baseline.ResultsAt baseline, no patient was at goal for all clinical parameters. After 1 year of treatment, all patients maintained goals present at baseline, and all achieved ≥ 2 goals. All 8 patients began step-wise dose reduction from 60 to 30 U/kg EOW between 15 and 18 months. By year 4 of treatment, all patients met goals for all 5 clinical parameters; therefore 100% achievement was seen for each of the 5 long-term, therapeutic goals.DiscussionIn this velaglucerase alfa Phase I/II and extension study, clinically meaningful achievement of each long-term, therapeutic goal was observed for each patient, despite dose reduction after 1 year. This is the first report of a cohort where all patients receiving ERT for type 1 Gaucher disease achieved all 5 of these long-term, therapeutic goals within 4 years of starting treatment and after ≥ 2 years dose reduction.     

Antiretroviral pill count and clinical outcomes in treatment‐naïve patients with HIV infection

Objectives

Treatment guidelines recommend single‐tablet regimens for patients with HIV infection starting antiretroviral therapy. These regimens might be as effective and cost less if taken as separate drugs. We assessed whether the one pill once a day combination of efavirenz, emtricitabine and tenofovir reduces the risk of disease progression compared with multiple‐pill formulations of the same regimen.

Methods

We selected treatment‐naïve patients starting one‐, two‐ or three‐pill formulations of this regimen in data from the Antiretroviral Therapy Cohort Collaboration. These patients were followed until an AIDS event or death or until they modified their regimen. We analysed these data using Cox regression models, then used our models to predict the potential consequences of exposing a future population to either a one‐pill regimen or a three‐pill regimen.

Results

Among 11 739 treatment‐naïve patients starting the regimen, there were 386 AIDS events and 87 deaths. Follow‐up often ended when patients switched to the same regimen with fewer pills. After the first month, two pills rather than one was associated with an increase in the risk of AIDS or death [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.01‐1.91], but three pills rather than two did not appreciably add to that increase (HR 1.19; 95% CI 0.84‐1.68). We estimate that 77 patients would need to be exposed to a one‐pill regimen rather than a three‐pill regimen for 1 year to avoid one additional AIDS event or death.

Conclusions

This particular single‐tablet regimen is associated with a modest decrease in the risk of AIDS or death relative to multiple‐pill formulations.

     

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment‐naïve patients with hepatitis C virus genotype 1 infection

Grazoprevir (GZR) is a second‐generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12‐week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response‐guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow‐up week 12 (HCV RNA <25 IU/mL) in the per‐protocol (PP) population (excluding patients with important protocol deviations). Twenty‐six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24‐week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24‐week arm who relapsed after follow‐up week 12. All three breakthrough patients had wild‐type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir‐based regimens (NCT01716156; protocol P039).     

Enzyme replacement therapy with taliglucerase alfa: 36‐month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase

Taliglucerase alfa is the first available plant cell‐expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB‐06‐002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB‐06‐002 who continued receiving taliglucerase alfa in extension Study PB‐06‐003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB‐06‐003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30–33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, ?1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), ?19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, ?51.5% (±8.1%; n = 10); and CCL18 concentration, ?36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment‐related adverse events were mild or moderate and transient. The 36‐month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661–665, 2016. © 2016 Wiley Periodicals, Inc.     

Hepatic steatosis and fibrosis in young men with treatment‐naïve chronic hepatitis B

Objectives: The clinical significance of liver steatosis has been studied because steatosis plays a role in the progression of liver fibrosis. Nevertheless, the impact of steatosis in the early stage of fibrosis in non‐obese young men with chronic hepatitis B (CHB) is poorly understood. Thus, the purpose of this study was to investigate the prevalence of hepatic steatosis, assess the relationship between hepatic steatosis and fibrosis and to assess the laboratory parameters for predicting clinically significant liver fibrosis in non‐obese young men with CHB. Methods: We prospectively evaluated liver biopsies in young male patients with CHBwith a serum alanine aminotransferase level of more than two times the upper limit of normal for at least 3 months before enrollment. Patients were excluded when they had co‐infection with another virus and prior antiviral treatment. Demographical, anthropometric and laboratory parameters were analysed. Liver steatosis, necroinflammation and fibrosis were also assessed. Results: A total of 86 young male patients with CHB were included in this study. The median age was 21 years (range, 20–26 years) and the median body mass index was 23.0 kg/m² (range, 18.0–28.3 kg/m²). Steatosis was present in 44 patients (51.2%). Significant fibrosis (beyond periportal fibrosis) was present in 50 patients (58.1%). Steatosis was associated with insulin, homeostasis model for insulin resistance (HOMA‐IR), total cholesterol and triglycerides. On multiple regression analysis, steatosis was independently associated with triglyceride and HOMA‐IR. Significant fibrosis was independently associated with γ‐glutamyltransferase (GGT) and necroinflammation activity. However, there was no significant association between significant fibrosis and the presence of steatosis. Conclusions: The prevalence of hepatic steatosis is a common finding in young male patients with CHB. Hepatic steatosis in CHB patients seems to be associated with insulin resistance, but it is not associated with hepatic fibrosis. GGT levels can provide useful information on the stage of CHB.     

Dexamethasone,rituximab and cyclophosphamide for relapsed and/or refractory and treatment‐naïve patients with Waldenstrom macroglobulinemia

The management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88^WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88^L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression‐free survival (PFS) and time‐to‐next‐therapy (TTNT) were 32 (95% confidence interval [CI]: 15–51) and 50 (95% CI: 35–60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23–not reached [NR]) and NR (95% CI: 37–NR), respectively. Twenty‐five (86%) of 29 genotyped patients harbored MYD88^L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well‐tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed‐duration option, with preliminary data suggesting efficacy independent of the patients’ MYD88 status.     

Simeprevir plus sofosbuvir for eight or 12 weeks in treatment‐naïve and treatment‐experienced hepatitis C virus genotype 4 patients with or without cirrhosis

The OSIRIS study investigated efficacy and safety of simeprevir plus sofosbuvir for eight or 12 weeks in hepatitis C virus (HCV) genotype 4‐infected patients with METAVIR F0‐F4 fibrosis. Sixty‐three patients (33 treatment‐naïve and 30 peg‐interferon/ribavirin (Peg‐IFN/RBV)‐experienced) enrolled in a partly randomized, open‐label, multicentre, phase IIa study. Patients with F0‐F3 fibrosis were randomized (1:1) into two groups (A1 and A2), stratified according to treatment experience and METAVIR score, to receive either eight weeks (Group A1, n=20) or 12 weeks (Group A2, n=20) of treatment. Patients with compensated cirrhosis (METAVIR F4) received 12 weeks of treatment (Group B, n=23). Treatment comprised simeprevir 150 mg and sofosbuvir 400 mg daily. The primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). Safety and tolerability were assessed throughout. Overall, 92% (95% CI: 82‐97) of patients achieved SVR12; 75% (15/20) in Group A1 and 100% in groups A2 and B. Patients who did not achieve SVR12 (n=5) experienced viral relapse during the first 32 days following treatment and were all prior Peg‐IFN/RBV null responders. The most commonly reported treatment‐emergent adverse events (TEAEs) were asymptomatic lipase increase (14%), pruritus (14%), headache (13%) and hyperbilirubinaemia (11%). No patients discontinued due to TEAEs. In conclusion, simeprevir plus sofosbuvir for 12 weeks achieved a 100% SVR rate in HCV genotype 4‐infected patients with or without compensated cirrhosis (ClinicalTrials.gov: NCT02278419). The AE and laboratory profile were favourable and consistent with previous data for simeprevir plus sofosbuvir in eight‐ and 12‐week regimens.     

Sofosbuvir plus ribavirin in treatment‐naïve patients with chronic hepatitis C virus genotype 1 or 3 infection in India

Until 2014, pegylated interferon plus ribavirin was the recommended standard of care for the treatment of chronic hepatitis C virus (HCV) infection in India. This open‐label phase 3b study, conducted across 14 sites in India between 31 March 2014 and 30 November 2015, evaluated the efficacy and safety of sofosbuvir plus ribavirin therapy among treatment‐naïve patients with chronic genotype 1 or 3 HCV infection. A total of 117 patients with genotype 1 or 3 HCV infection were randomized 1:1 to receive sofosbuvir 400 mg and weight‐based ribavirin (1000 or 1200 mg) daily for 16 or 24 weeks. Among those with genotype 1 infection, the primary efficacy endpoint of sustained virologic response at 12 weeks post‐treatment (SVR12) was reported in 90% (95% confidence intervals [CI], 73‐98) and 96% (95% CI, 82‐100) of patients following 16 and 24 weeks of treatment, respectively. For patients with genotype 3 infection, SVR12 rates were 100% (95% CI, 88‐100) and 93% (95% CI, 78‐99) after 16 and 24 weeks of therapy, respectively. Adverse events, most of which were mild or moderate in severity, occurred in 69% and 57% of patients receiving 16 and 24 weeks of treatment, respectively. The most common treatment‐emergent adverse events were asthenia, headache and cough. Only one patient in the 24‐week group discontinued treatment with sofosbuvir during this study. Overall, sofosbuvir plus ribavirin therapy achieved SVR12 rates ≥90% and was well tolerated among treatment‐naïve patients with chronic genotype 1 or 3 HCV infection in India.