Clinical considerations for biosimilar antibodies

Biosimilar agents are approximate copies of branded biologic therapies. Since the first biosimilar was authorized in the European Union in 2006, fifteen additional agents have been approved by the European Medicines Agency, including two biosimilar monoclonal antibodies (mAbs). Biosimilar mAbs represent a distinct class given their large molecular size, complex protein structure, and post-translational modifications. While guidelines have been established for the development, approval, and use of biosimilars, further scrutiny and discussion is necessary to fully understand their potential impact on clinical outcomes. This review takes a critical look at the structural complexity of biosimilar mABs, the feasibility of indication extrapolation, the impact of product variability on immunogenicity, the importance of comprehensive pharmacovigilance, and the potential for ongoing pharmacoeconomic impact

Ibrutinib-A double-edge sword in cancer and autoimmune disorders

Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton’s tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.CLL Global Research FoundationManuscrip

Cumulative overall survival (OS) (solid black line) and progression-free survival (PFS) (solid grey line) from the start of study treatment until death (OS) and clinical and/or radiological signs of disease progression (PFS), respectively, for all patients in the study.

<p>Number of evaluable patients for OS = 33 out of 33, for PFS = 29 out of 33.</p

CONSORT Flow Diagram for the patients screened for and enrolled in part II.

<p>Corresponding data for patients enrolled in part I, has been published in Ullenhag GJ et al, PLOS ONE, 2015; 10(4).</p

Temporary cessation of ibrutinib results in reduced grade 3‐4 infections and durable remissions—Interim analysis of an on‐off‐repeat Phase 1b/2 study in patients with chronic lymphocytic leukemia

Abstract Ibrutinib is used continuously in CLL. This phase 1b/2 study interim analysis explored on‐off‐repeat dosing to reduce toxicity. After 12 months, 16/22 patients (73%) remained in first off‐phase irrespective if initial CR/PR or TP53 aberration. Grade 3‐4 infections were reduced from 55% to 5% during a similarly long off‐phase (P < .01). Treg and exhausted T‐cells increased (P = .01). Six patients restarted ibrutinib at early progression and remain drug‐sensitive. Our interim analysis shows a durable off‐phase in most patients, with reduced infections and cost‐saving potential. If toxicity‐driven permanent cessation of ibrutinib will be affected will be explored in the extended study