4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice.

Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal, dermal, and pulmonary SLE manifestations of MRL(Fas)lpr mice. However, even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts, which were significantly reduced in CYC-treated mice. Together, the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence, DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Pelmeg®, a pegfilgrastim biosimilar in healthy subjects.

A pharmacokinetics (PK)/pharmacodynamics (PD) study (EudraCT number 2015-002966-21) was conducted to investigate the biosimilarity of Pelmeg® (pegfilgrastim), a biosimilar to EU-authorized Neulasta®, which is used in the clinic for prevention of chemotherapy-induced neutropenia. The single-dose, randomized, double-blind, two-way crossover study comprised 171 healthy male subjects, receiving Pelmeg and Neulasta (6 mg as subcutaneous injection) in a sequential manner. Primary PK endpoints were the area under the concentration curve from time zero to last measurable concentration (AUC0-last) and the maximum concentration (Cmax). The primary PD endpoint was the area under the effect curve (AUEC0-last) for absolute neutrophil count (ANC). Safety and immunogenicity were also assessed. Comparability was demonstrated for both PK endpoints, with geometric mean ratios (test/reference) for AUC0-last and Cmax of 95.2% and 92.8%, respectively. The corresponding confidence intervals (CIs; 94.3%) were [86.6%;104.7%] for AUC0-last and [84.4%;102.2%] for Cmax, both being within the equivalence margin of 80.0% to 125.0%. Likewise, PD comparability was demonstrated, with the geometric mean ratio (test/reference) of AUEC0-last of 100.2%, with a corresponding CI (95%) of 98.7%-101.8%. No clinically meaningful differences were observed for safety and immunogenicity between Pelmeg and Neulasta. Pelmeg was found to be highly similar to the reference product.

Pharmacodynamics, safety, and immunogenicity of Pelmeg®, a pegfilgrastim biosimilar in healthy subjects.

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU-authorized Neulasta®. The multiple-dose, randomized, double-blind, two-sequence, and three-period cross-over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T-T-R vs R-R-T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose-response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0-last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti-drug antibody (ADA)-positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0-last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%-111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg.