Anton Buchner

The gastrointestinal tolerability of the LOX/COX inhibitor, licofelone, is similar to placebo and superior to naproxen therapy in healthy volunteers: results from a randomized, controlled trial.

OBJECTIVES:Concerns exist over the safety of conventional nonsteroidal antiinflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors. In experimental models, licofelone, a competitive inhibitor of 5-lipoxygenase (5-LOX) and COX-1/-2, has been shown to have good gastrointestinal and general tolerability and analgesic and antiinflammatory properties. The aim of the present endoscopy trial was to investigate the gastroduodenal tolerability of licofelone compared to placebo and naproxen in healthy volunteers.METHODS:In this randomized, parallel-group trial, healthy volunteers received licofelone 200 mg b.i.d. (n = 30), licofelone 400 mg b.i.d. (n = 30), naproxen 500 mg b.i.d. (n = 30), or placebo (n = 31). Tolerability was assessed by gastro/duodenoscopy following 4 wk of treatment. Laboratory parameters and the incidence of ulcers and adverse events were recorded.RESULTS:Ulcers were observed in 20% of the naproxen-treated volunteers, compared with 0% of those receiving licofelone 200 mg, licofelone 400 mg, and placebo (p = 0.024). Posttreatment mean gastric Lanza scores were similar for volunteers who received placebo or either dose of licofelone, while Lanza scores were significantly worse following naproxen therapy (p < 0.00001). The gastric mucosa was normal in 93%, 89%, and 90% of volunteers who received licofelone 200 mg, licofelone 400 mg, or placebo, respectively, compared with 37% of volunteers receiving naproxen. The incidence of adverse events did not differ significantly between licofelone 200 mg or naproxen therapy. No clinically relevant changes in laboratory parameters were observed with licofelone or naproxen therapy.CONCLUSIONS:The results from this trial indicate that licofelone has a potential gastrointestinal safety advantage over conventional NSAID therapy, as licofelone was associated with significantly superior gastric tolerability and a lower incidence of ulcers compared with naproxen in healthy volunteers. Further trials will be required to investigate the safety and efficacy of licofelone in the treatment of diseases such as osteoarthritis.

Epoetin Theta in Anaemic Cancer Patients Receiving Platinum-Based Chemotherapy: A Randomised Controlled Trial.

Introduction Recombinant human erythropoietin (r-HuEPO) is used to treat symptomatic anaemia due to chemotherapy. A new r-HuEPO, Epoetin theta (Eporatio®), was investigated and compared to placebo and Epoetin beta in a randomised, double-blind clinical trial in adult cancer patients receiving platinum-based chemotherapy, using a fixed weekly starting dose of 20,000 IU Epoetin theta. The primary efficacy endpoint was the responder rate (complete Hb response, Hb increase ≥ 2 g/dL). Research Design and Methods 223 patients were randomised to s.c. treatment for 12 weeks with either Epoetin theta (n = 76) once per week, Epoetin beta (n = 73) three times per week or placebo (n = 74). The starting dose was 20,000 IU once weekly Epoetin theta or 450 IU/kgBW per week Epoetin beta administered in 3 equal weekly doses. Results In the Epoetin theta group were significantly more responders than in the placebo group (65.8 vs. 20.3%, P < 0.0001). Epoetin beta was also more effective than placebo (71.2 vs. 20.3%, P < 0.0001). The mean weekly dose at the time of complete Hb response was lower in the Epoetin theta group (30,000 IU) than in the Epoetin beta group (42,230 IU). Epoetin theta was clearly more effective than placebo. Conclusion This small study showed, that Epoetin theta is a safe and effective treatment of symptomatic anaemia due to platinum-based chemotherapy in cancer patients.

Efficacy and Safety of Balugrastim Compared With Pegfilgrastim in Patients With Breast Cancer Receiving Chemotherapy

BACKGROUND Recombinant granulocyte colony-stimulating factors (G-CSFs) reduce the incidence and duration of chemotherapy-induced neutropenia and febrile neutropenia when given as adjunct therapy to patients receiving myelosuppressive chemotherapy. Balugrastim is a long-acting G-CSF composed of a genetic fusion between recombinant human serum albumin and G-CSF. We compared the efficacy and safety of balugrastim and pegfilgrastim, a long-acting pegylated recombinant G-CSF, in patients with breast cancer who were scheduled to receive chemotherapy. PATIENTS AND METHODS In this double-blind randomized phase III trial, patients with ≥ 1.5 × 10(9) neutrophils/L were randomly assigned to subcutaneous injections of balugrastim 40 mg (n = 153) or pegfilgrastim 6 mg (n = 151). The primary efficacy end point was the duration of severe neutropenia (DSN) (days with an absolute neutrophil count [ANC] < 0.5 × 10(9) cells/L) during cycle 1. Efficacy analyses were performed in the per-protocol (PP) population. In a separate open-label single-arm study, newly recruited patients (n = 77) received balugrastim 40 mg and were included in the safety analysis. RESULTS The mean DSN in cycle 1 was 1.1 days in the balugrastim group and 1.0 days in the pegfilgrastim group (95% confidence interval [CI], -0.13-0.37). Two and 4 patients, respectively, had febrile neutropenia during cycle 1. Twenty percent of patients in the balugrastim group and 19% in the pegfilgrastim group had adverse events (AEs) considered to be related to study medication; 3.9% and 4.7% of patients, respectively, experienced serious AEs. CONCLUSIONS This study demonstrates the comparable safety and efficacy profile of balugrastim and pegfilgrastim and the noninferiority of balugrastim for reduction in DSN. There were no unexpected safety events.

Epoetin Theta with a New Dosing Schedule in Anaemic Cancer Patients Receiving Nonplatinum-Based Chemotherapy: A Randomised Controlled Trial

Introduction Recombinant human erythropoietin (r-HuEPO) is used to treat symptomatic anaemia due to chemotherapy. A new r-HuEPO, Epoetin theta (Eporatio®), was investigated and compared to placebo in a randomised, double-blind clinical trial in adult cancer patients receiving nonplatinum-based chemotherapy. The primary efficacy endpoint was the responder rate (complete haemoglobin (Hb) response, i.e., Hb increase ≥2 g/dl) without the benefit of a transfusion within the previous 4 weeks. Research Design and Methods 186 patients were randomised to s.c. treatment for 12 weeks with either Epoetin theta (N = 95) or placebo (N = 91). The starting dose was 20,000 IU once weekly Epoetin theta or placebo. Results The incidence of complete Hb responders was significantly higher in the Epoetin theta group than in the placebo group (72.6 vs. 25.3%, P < 0.0001). More patients in the placebo group than in the Epoetin theta group received blood transfusions after randomisation (23 patients, 25.3% vs. 13 patients, 13.7%, P = 0.0277). The majority of patients with a complete Hb response had 20,000 IU/week as their maximum dose prior to response, indicating that a dose of 20,000 IU is an appropriate starting dose. The overall frequencies of adverse events (AEs) were similar in both treatment groups. Hypertension was the only AE that was more frequent in the Epoetin theta group compared to the placebo group (8.4 vs. 1.1%). Conclusions Epoetin theta showed a superior efficacy to placebo in terms of complete Hb response without blood transfusion within the previous 4 weeks. Treatment with Epoetin theta resulted in a statistically significant increase in mean haemoglobin levels compared to placebo. The overall frequencies of adverse events were similar in both treatment groups.

Epoetin theta: efficacy and safety of subcutaneous administration in anemic pre-dialysis patients in the maintenance phase in comparison to epoetin beta

Abstract Objective: To compare the efficacy and safety of epoetin theta and epoetin beta in anemic patients with chronic kidney disease (CKD) not yet receiving dialysis and previously on stable maintenance therapy with epoetin beta. Methods: In this multicenter, randomized, controlled, double-blind, non-inferiority study, 288 patients were treated subcutaneously (s.c.) for 24 weeks with epoetin theta (n = 193) or epoetin beta (n = 95). The primary efficacy endpoint was change in hemoglobin (Hb) from a 2-week baseline period to end of treatment (12-week efficacy evaluation period [EEP], weeks 15–26). The non-inferiority limit was 1.0 g/dL (2-sided alpha = 0.05). Weekly doses of epoetin required to maintain Hb levels, dose changes, safety, tolerability, and immunogenicity were also evaluated. Clinical trial registration: EudraCT No. 2005-000142-37 Results: Mean Hb values were comparable in both groups at baseline and during the 24-week treatment period. The estimated treatment difference between groups from baseline to EEP was 0.01 g/dL (95% confidence interval: −0.20, 0.22; p = 0.9207 (ANCOVA)), indicating that epoetin theta was non-inferior to epoetin beta. The weekly doses of epoetin theta or epoetin beta were nearly the same and the change from baseline to EEP in patients who switched to epoetin theta (36.6 to 30.0 IU/kgBW) was comparable to those continuing epoetin beta therapy (37.7 to 28.3 IU/kgBW). The profile and the frequency of adverse drug reactions (ADRs) were comparable in both groups (17.1% epoetin theta; 14.7% epoetin beta). The most common ADR was hypertension. No patient developed anti-erythropoietin antibodies. Conclusions: Epoetin theta (s.c.) has efficacy comparable with epoetin beta (s.c.) in pre-dialysis patients with renal anemia based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was also comparable. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes.

Epoetin theta: efficacy and safety of IV administration in anaemic haemodialysis patients in the maintenance phase in comparison to epoetin beta

Abstract Objective: To compare the efficacy and safety of epoetin theta and epoetin beta in anaemic patients with chronic kidney disease, undergoing haemodialysis and previously on stable maintenance therapy with epoetin beta. Methods: In this multicentre, randomised, controlled, double-blind study 270 haemodialysis patients were treated intravenously (i.v.) for 24 weeks with either epoetin theta (n = 180) or epoetin beta (n = 90). The primary efficacy endpoint was the change in haemoglobin (Hb) from baseline to end of treatment (efficacy evaluation period, EEP, weeks 15–26). Hb levels, weekly doses of epoetin theta or epoetin beta required to maintain Hb levels, dose changes, safety, tolerability and immunogenicity were evaluated. Clinical trial registration: EudraCT No. 2005-000143-28 Results: Mean Hb values were similar in both treatment groups at baseline and during the 24-weeks treatment period. The estimated treatment difference between epoetin theta and epoetin beta from baseline to EEP was −0.01 g/dL (95% confidence interval: −0.24, 0.21), p = 0.9021, indicating that the difference between both groups was not statistically significant. The weekly doses of epoetin theta or epoetin beta required to maintain Hb levels were nearly the same. The changes from baseline to EEP in patients who switched to treatment with epoetin theta (95.5–99.7 IU/kgBW) were smaller than in patients staying on their epoetin beta therapy (89.0–98.0 IU/kgBW). The profile and the frequency of adverse drug reactions (ADRs) were similar in both treatment groups (21.7% epoetin theta; 22.2% epoetin beta). The most common ADRs were hypertension, headache and arteriovenous fistula thrombosis. None of the patients developed anti-erythropoietin antibodies. Conclusions: Epoetin theta (i.v.) has a similar efficacy compared to epoetin beta (i.v.) in haemodialysis patients based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was similar in both groups. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes.

Lipegfilgrastim: pharmacodynamics and pharmacokinetics for body-weight-adjusted and 6 mg fixed doses in two randomized studies in healthy volunteers.

Abstract Objective: Two phase I, single-blind (subject blinded to treatment), randomized studies were conducted to assess the pharmacodynamics, pharmacokinetics, safety, and tolerability of lipegfilgrastim compared with pegfilgrastim in healthy adult volunteers. Methods: Study 1 consisted of a pilot safety phase (N = 8) during which subjects received a single body-weight-adjusted subcutaneous dose of lipegfilgrastim 25 µg/kg and a dose escalation phase (N = 45) wherein subjects received lipegfilgrastim 50 or 100 μg/kg or pegfilgrastim 100 μg/kg. Study 2 was a single-blind, fixed-dose study (N = 36) comparing subcutaneous lipegfilgrastim 6 mg and pegfilgrastim 6 mg. Results: Cumulative exposure (AUC0–tlast and AUC0–∞) and peak exposure (Cmax) were higher for lipegfilgrastim than pegfilgrastim after both weight-adjusted and fixed dosing. In both studies, the terminal elimination half-life of lipegfilgrastim was 5–10 hours longer than the terminal elimination half-life for pegfilgrastim at the maximum dose, and the time to maximum serum concentration (tmax) was observed later for lipegfilgrastim than for pegfilgrastim. The area over the baseline effect curve (AOBEC) for absolute neutrophil count (ANC) was approximately 30% greater after lipegfilgrastim dosing compared with the same dose of pegfilgrastim at the maximum dose. Both drugs were well tolerated, with a similar occurrence of adverse events between treatment groups. Key limitations of these studies include the small numbers of subjects and differences in dosage regimens between the two studies. Conclusions: In these studies, lipegfilgrastim provided a longer-lasting increase in ANC compared with pegfilgrastim at an equivalent dose, without increasing the peak ANC values. This may reflect the higher cumulative exposure and slower clearance (therefore longer body residence) of lipegfilgrastim. These data support the use of single-dose lipegfilgrastim 6 mg in subsequent phase III trials as prophylactic treatment for patients receiving myelosuppressive chemotherapy.