Biosimilars 2.0: Guiding principles for a global “patients first” standard

In the European Union, biosimilar products have been approved since 2006 under an abbreviated pathway that leverages their similarity to an existing “reference” biological product. The products approved to date are based on recombinant versions of endogenous proteins with well-understood structures and pharmacology, but complicated safety and immunogenicity profiles. The period during the 2000s that included the first reviews, approvals, sale and use of biosimilars is referred to herein as “Biosimilars 1.0.” Over the next several years, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. A global market for biosimilars is developing and this may well foreshadow the beginning of the second era of product development. This Biosimilars 2.0 period will likely be characterized by the development of complex products, global harmonization of standards and the increasing demand for long-term monitoring of pharmaceuticals. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, Biosimilars 2.0 manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership, to outline the appropriate standards for these products and to facilitate increased access while meeting patients' needs

The Emergence of Biosimilar Insulin Preparations—A Cause for Concern?

Several biopharmaceuticals, including insulin and insulin analogs, are, or shortly will be, off-patent, thereby providing an opportunity for companies to attempt to manufacture "copies" commonly referred to as biosimilars and also known as follow-on biologics. Reassurance that such copy biologics are equally safe and effective as the conventional products is essential. It is important for the clinician to consider what information is therefore necessary for such assurances. Biopharmaceuticals, produced from living organisms and manufactured by complex processes, differ in many respects from chemically derived drugs. The biological source materials and manufacturing processes for non-innovator biologics may differ considerably from those used for producing the innovator substance. Differences between innovator and non-innovator products can be identified analytically (e.g., batch-to-batch consistency, product stability along side clinical safety). This provides a strong argument for caution before automatic substitution of conventional products (e.g., insulin by biosimilars). Several non-innovator insulins, including insulin analogs (while still patent-protected), are already available in many countries. Many of these lack rigorous regulations for biosimilar approval and pharmacovigilance. Recently an application for a biosimilar recombinant human insulin was withdrawn by the European Medicines Agency because of safety and efficacy concerns. Therefore, every biosimilar insulin and insulin analog should be assessed by well-defined globally harmonized preclinical and clinical studies followed by post-marketing pharmacovigilance programs, in the interest of people with diabetes worldwide

Involvement of Alpha-PAK-Interacting Exchange Factor in the PAK1–c-Jun NH(2)-Terminal Kinase 1 Activation and Apoptosis Induced by Benzo[a]pyrene

Benzo[a]pyrene [B(a)P], a potent procarcinogen found in combustion products such as diesel exhaust and cigarette smoke, has been recently shown to activate the c-Jun NH(2)-terminal kinase 1 (JNK1) and induce caspase-3-mediated apoptosis in Hepa1c1c7 cells. However, the molecules of the signaling pathway that control the mitogen-activated protein kinase cascades induced by B(a)P and the interaction between those and apoptosis by B(a)P have not been well defined. We report here that B(a)P promoted Cdc42/Rac1, p21-activated kinase 1 (PAK1), and JNK1 activities in 293T and HeLa cells. Moreover, alpha-PAK-interacting exchange factor (α PIX) mRNA and its protein expression were upregulated by B(a)P. While overexpression of an active mutant of α PIX (ΔCH) facilitated B(a)P-induced activation of Cdc42/Rac1, PAK1, and JNK1, overexpression of mutated αPIX (L383R, L384S), which lacks guanine nucleotide exchange factor activity, SH3 domain-deleted αPIX (Δ SH3), which lacks the ability to bind PAK, kinase-negative PAK1 (K299R), and kinase-negative SEK1 (K220A, K224L) inhibited B(a)P-triggered JNK1 activation. Interestingly, overexpression of αPIX (Δ CH) and a catalytically active mutant PAK1 (T423E) accelerated B(a)P-induced apoptosis in HeLa cells, whereas αPIX (Δ SH3), PAK1 (K299R), and SEK 1 (K220A, K224L) inhibited B(a)P-initiated apoptosis. Finally, a preferential caspase inhibitor, Z-Asp-CH2-DCB, strongly blocked the αPIX (Δ CH)-enhanced apoptosis in cells treated with B(a)P but did not block PAK1/JNK1 activation. Taken together, these results indicate that αPIX plays a crucial role in B(a)P-induced apoptosis through activation of the JNK1 pathway kinases