Policies for biosimilar uptake in Europe : an overview

Background: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. Objectives: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. Methods: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. Results: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. Conclusions: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market

Reengineering the collision coupling and diffusion mode of the A 2A-adenosine receptor: palmitoylation in helix 8 relieves confinement

The A(2A)-adenosine receptor undergoes restricted collision coupling with its cognate G protein G(s) and lacks a palmitoylation site at the end of helix 8 in its intracellular C terminus. We explored the hypothesis that there was a causal link between the absence of a palmitoyl moiety and restricted collision coupling by introducing a palmitoylation site. The resulting mutant A(2A)-R309C receptor underwent palmitoylation as verified by both mass spectrometry and metabolic labeling. In contrast to the wild type A(2A) receptor, the concentration-response curve for agonist-induced cAMP accumulation was shifted to the left with increasing expression levels receptor, an observation consistent with collision coupling. Single particle tracking of quantum dot-labeled receptors confirmed that wild type and mutant A(2A) receptor differed in diffusivity and diffusion mode; agonist activation resulted in a decline in mean square displacement of both receptors, but the drop was substantially more pronounced for the wild type receptor. In addition, in the agonist- bound state, the wild type receptor was frequently subject to confinement events (estimated radius 110 nm). These were rarely seen with the palmitoylated A(2A)-R309C receptor, the preferred diffusion mode of which was a random walk in both the basal and the agonist-activated state. Taken together, the observations link restricted collision coupling to diffusion limits imposed by the absence of a palmitoyl moiety in the C terminus of the A(2A) receptor. The experiments allowed for visualizing local confinement of an agonist-activated G protein- coupled receptor in an area consistent with the dimensions of a lipid raft

Recruitment of a cytoplasmic chaperone relay by the A(2A) adenosine receptor

The adenosine A(2A) receptor is a prototypical rhodopsin-like G protein-coupled receptor but has several unique structural features, in particular a long C terminus (of >120 residues) devoid of a palmitoylation site. It is known to interact with several accessory proteins other than those canonically involved in signaling. However, it is evident that many more proteins must interact with the A(2A) receptor, if the trafficking trajectory of the receptor is taken into account from its site of synthesis in the endoplasmic reticulum (ER) to its disposal by the lysosome. Affinity-tagged versions of the A(2A) receptor were expressed in HEK293 cells to identify interacting partners residing in the ER by a proteomics approach based on tandem affinity purification. The receptor-protein complexes were purified in quantities sufficient for analysis by mass spectrometry. We identified molecular chaperones (heat-shock proteins HSP90 and HSP70-1A) that interact with and retain partially folded A(2A) receptor prior to ER exit. Complex formation between the A(2A) receptor and HSP90 (but not HSP90) and HSP70-1A was confirmed by co-affinity precipitation. HSP90 inhibitors also enhanced surface expression of the receptor in PC12 cells, which endogenously express the A(2A) receptor. Finally, proteins of the HSP relay machinery (e.g. HOP/HSC70-HSP90 organizing protein and P23/HSP90 co-chaperone) were recovered in complexes with the A(2A) receptor. These observations are consistent with the proposed chaperone/coat protein complex II exchange model. This posits that cytosolic HSP proteins are sequentially recruited to folding intermediates of the A(2A) receptor. Release of HSP90 is required prior to recruitment of coat protein complex II components. This prevents premature ER export of partially folded receptors

Policies for biosimilar uptake in Europe: an overview

Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe.status: publishe

The Expiry of Humira® Market Exclusivity and the Entry of Adalimumab Biosimilars in Europe: An Overview of Pricing and National Policy Measures

From October 2018, adalimumab biosimilars could enter the European market. However, in some countries, such as Netherlands, high discounts reported for the originator product may have influenced biosimilar entry. The aim of this paper is to provide a European overview of (list) prices of originator adalimumab, before and after loss of exclusivity; to report changes in the reimbursement status of adalimumab products; and discuss relevant policy measures. Experts in European countries received a survey consisting of three parts: 1) general financing/co-payment of medicines, 2) reimbursement status and prices of originator adalimumab, and availability of biosimilars, and 3) policy measures related to the use of adalimumab. In May 2019, adalimumab biosimilars were available in 24 of the 30 countries surveyed. Following introduction of adalimumab biosimilars, a number of countries have made changes in relation to the reimbursement status of adalimumab products. Originator adalimumab list prices varied between countries by a factor of 2.8 before and 4.1 after loss of exclusivity. Overall, list prices of originator adalimumab decreased after loss of exclusivity, although for 13 countries list prices were unchanged. When reported, discounts/rebates on originator adalimumab after loss of exclusivity ranged from 0% to approximately 26% (Romania), 60% (Poland), 80% (Denmark, Italy, Norway), and 80–90% (Netherlands), leading to actual prices per pen or syringe between €412 (Finland) and €50 – €99 (Netherlands). To leverage competition following entry of biosimilar adalimumab, only a few countries adopted measures specifically for adalimumab in addition to general policies regarding biosimilars. In some countries, a strategy was implemented even before loss of exclusivity (Denmark, Scotland), while others did not report specific measures. Even though originator adalimumab is the highest selling product in the world, few countries have implemented specific policies and practices for (biosimilar) adalimumab. Countries with biosimilars on the market seem to have competition lowering list or actual prices. Reported discounts varied widely between countries

Policies for biosimilar uptake in Europe: An overview

markdownabstract__Background__ Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. __Objectives__ The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. __Methods__ An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. __Results__ In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. __Conclusions__ Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market