Zonisamide

Zonisamide is a second-generation antiepileptic drug characterized by a few antiepileptic indications, with an acceptable interaction profile in polytherapy. Zonisamide has an acceptable tolerability profile in patients with epilepsy, with depression, irritability, agitation and psychosis as the most commonly reported psychiatric adverse effects. Zonisamide has no approved indications or clinical uses in psychiatry, as initial findings from uncontrolled studies suggesting effectiveness in the treatment of patients with bipolar disorder did not find confirmation. There is preliminary evidence for possible usefulness of zonisamide in the treatment of patients with obesity and psychotropic-associated weight gain, as well as alcohol dependence and withdrawal.

An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial

Objective.Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.Methods.All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.Results.Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.Conclusion.Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD. Trial registration: ClinicalTrials.gov; www.clinicaltrials.govNCT01933334.

L-Asparaginase Loaded Inside Red Cells Has An Acceptable Tolerability Profile On Bilirubin Value

L-asparaginase has been a major drug in the treatment of acute lymphoblastic leukemia (ALL) over the past decades, its efficacy has been demonstrated in a broad range of patient clinical profiles. However frequence and severity of toxicities, of which allergic reactions, have been a major drawback. L-asparaginase loaded inside homologous red cells, suspended in SAG-mannitol preservative solution, (GRASPA) is a new available formulation for administering L-asparaginase in combination with standard chemotherapy in different ALL populations, including frail patients older than 55years. Tolerability and efficacy of GRASPA in patients with ALL have been investigated in successive clinical trials (GRASPALL 2005-01 and GRASPALL/GRAALL-SA2-2008). The global toxicity of this new L-asparaginase formulation is decreased, in all age groups, with fewer hypersensitive reactions. A significant reduction of the coagulation disorders in patients <55 years old has also been reported. The pharmacokinetics is improved, with a half-life of about 30 days compared to 1 day for the free formulation. GRASPA has been proposed as a new approach to maintain the complete activity of L-asparaginase while reducing its antibody mediated toxicity. The red blood cells (RBC) act as a micro bioreactor and protect the enzyme against circulating antibodies. Plasma asparagine diffuses through the RBC membrane to the intra cellular compartment where it is cleaved by the entrapped L-asparaginase. In addition, encapsulation into RBC has been shown to extend the duration of drug action, allowing a reduction in the number of injections. Hepatic toxicity has often been reported with regular L-aparaginase associated with chemotherapy in ALL patients. Therefore this, and more specifically the occurrence of hyperbilirubinemia, with GRASPA, need to be studied. Indeed, bilirubin is a major breakdown product of hemoglobin. Hemoglobin is derived from red cells that have outlived their natural life and subsequently have been trapped inside the spleen. During splenic degradation of RBC, hemoglobin is separated from iron and cell membrane components. Hemoglobin is then transferred to the liver where it undergoes its further metabolic transformations in a process called conjugation. As the liver becomes irritated, the total bilirubin may rise and this lead to hyperbilirubinemia. GRASPA is containing a weak fraction of extracellular hemoglobin (2 g/dl maximum the day of injection), and the red cell half-life has been shown similar to that of non-processed red cells (about 30 days). We investigated in our clinical studies, whether there is any relationship between GRASPA administration and the occurrence of hyperbilirubinemia. In a first study in 12 relapsed-ALL patients <55 years old, at the dosages of 100 and 150IU/kg, we observed 1/6 case of transient hyperbilirubinemia (due to cytolysis) in the adult population and 0/6 case in the children stratum. In the same study, 1/3 adults (due to cytolysis) and 2/3 children, from the control group receiving the native E.Coli L-asparaginase, developped hyperbilirubinemia. In a non-randomised study, 27 newly diagnosed ALL patients over 55 year-old were investigated. At the same dosages, 4/27 experienced hyperbilirubinemia (including 1 with increasing bilirubinemia before treatment). These results are in accordance with data from the literature (W. Stock, 2011, leuk. & lymph.). Interestingly, GRASPA was also administrated in monotherapy in 12 patients with pancreatic carcinoma. Results showed that up to the highest dose tested (150IU/kg) all patients had normal bilirubinemia values. In conclusion, using red cells to vehicle L-asparaginase does not increase the risk of hyperbilirubimenia, and has an acceptable tolerability profile for fragile patients. Disclosures: Plisson: Orphan Europe: Employment. Hunault:ERYTECH Pharma: Principal Investigator Other. Thomas:ERYTECH Pharma: Principal Investigator Other; Orphan Europe: Consultancy. Legay:ERYTECH Pharma: Principal Investigator Other. Bertrand:ERYTECH Pharma: Principal Investigator Other. Andre:ERYTECH Pharma: clinical trial investigator Other. Godfrin:ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 3-year (yr) follow-up (f/u).

6509^ Background: In ENESTnd, nilotinib significantly reduced progression to AP/BC and demonstrated superior rates of MMR, MR4, and MR4.5 vs imatinib with f/u of 2 yrs. Methods: 846 pts with Ph+ CML-CP were randomized to nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283). Here, we report 3-yr f/u data. Results: Both nilotinib doses continued to demonstrate significantly higher rates of MMR, MR4, and MR4.5 vs imatinib. In a landmark analysis, pts with BCR-ABL transcript levels ≤ 10% at 3 months (mo) had a higher probability of achieving MMR by 1 and 2 yrs vs pts with transcript levels > 10%. No new progressions occurred on treatment since the 2-yr analysis; rates of progression to AP/BC including events on treatment (n = 2, 3, 12) and those occurring both on treatment and after discontinuation (n = 9, 6, 19) were significantly lower for nilotinib 300 mg BID and nilotinib 400 mg BID vs imatinib, respectively. At 3 yrs, OS considering only CML-related deaths was significantly higher for nilotinib vs imatinib. The safety profiles of nilotinib and imatinib were similar to those at 2 yrs. Conclusions: 3-yr f/u confirms the superiority of nilotinib vs imatinib and an acceptable tolerability profile for the treatment of pts with newly diagnosed Ph+ CML-CP. [Table: see text]