Global Nephrology

Biosimilar Epoetin

Since nearly one quarter of all the hits to this blog come from outside the US we are starting a regular  feature on a global issue. The first article is on epoetin biosimilars. This topic should have some interest to Europeans and Americans. In Europe, 3 epoetin biosmilars have been on the market for the past few years and more are likely to be introduced soon, whereas in the US, epoetin biosmilars are likely to be introduced in the next 3 to 5 years as Amgen's US patent for epoetin expires. In fact, biosimilar legislation in the U.S. has already been passed (≈ 2 years ago).

In the developing world, there are over 2 dozen epoetin biosimilars on the market. However, while the choice is great for patients, the introduction of biosimilars do pose some challenges, and their introduction globally have provided some lessons. 

COMMENTARY 

Biologics have transformed the treatment of many human diseases, including the treatment of anemia, rheumatoid arthritis, multiple sclerosis, and cancer. However, their development has also spawned the introduction of similar biologic agents or biosimilars that are marketed to have similar efficacy and safety as the original (innovator) product.

A Biosimilar is a biologic that is similar to, but not the same as the approved innovator biologic with regards to bioequivalence or therapeutic equivalence. An innovator biologic is the originally licensed or registered compound. (Huub Schellekens has an excellent review in NDT that is definitely worth reading).

In most cases, the most important reason for using a biosimilar is its price. Biosimilar products are frequently priced at 40 to 70% below the price of the innovator molecule. This has been true for epoetin also. 

3 lessons have been learnt from the launch of epoetin biosimilars:

1. The manufacturing of epoetin biosimilars is not identical to the epoetin innovator molecules (epogen/darbepoetin).

Biosimilar epoetins are large heterogeneous compounds that are produced after complex production and purification processes, and are relatively unstable with a complex mode of action. The manufacturing process could result in variability in the protein or its formation: for example, the choice of the expression vector, the cell fermentation process, selection of the host cell line, the protein purification process, and the sterile filling and drug product steps. Subtle variations in temperature, cell culture conditions or even transport or storage conditions might result in significant differences in the clinical efficacy, biological activity and safety with enhanced immunogenicity of the product in some cases.

One or more problems in the manufacturing process of the innovator epoetin-α (marketed in Europe as Eprex®, Janssen-Ortho Biotech) resulted in several hundred pure red cell aplasia (PRCA) cases between 2001 and 2003 in CKD patients. The consensus is that PRCA resulted from lechates from rubber lined pre-filled syringes leaking into the epoetin preparation and causing epoetin aggregation (the subcutaneous route of administration epoetin also seemed to play a role). With the modifications in the manufacturing process a >80% reduction in the incidence of epoetin-related PRCA was noted. 

2. Efficacy and Safety of epoetin biosmilars is not necessarily the same as that of the innovator epoetin.
With the inability to reproduce an identical molecule efficacy measurements and standardized analytical and pre-clinical tests for biosimilars are likely to be insufficient to demonstrate comparability of two biological products.

In a recent study (1), we procured biosimilar epoetin samples from pharmacies in Korea, Thailand, Vietnam, India, Philippines, Indonesia, Iran, Yemen, Jordan, Lebanon and Columbia. Several biogeneric epoetin’s from India were included (for example, Vintor, Wepox, and Zyrop). We observed variable physical characteristics with respect to pH, osmolality and isoelectric charge for the biogeneric epoetins compared to the invovator epoetin. These biosimilar epoetins revealed varying in vitro and in vivo potencies. As well, there was variability in the degree of aggregation of the epoetin molecule -- over 1/3rd of the epoetin biosimilars in our sample had >3% aggregation. One of the epoetin preparations was contaminated with endotoxin.

3. Countries with biosimilars need a robust pharmacovigilance system in place

What is pharmacovigilance? It is the science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short-term side effects of medicines. Why is it needed? Because at the time of approval clinical trial data are available on only limited numbers of patients treated for relatively short periods (e.g., 500 to 1500 patients for 1 to 3 years). Once a product is marketed, large numbers of patients may be exposed, including patients who were not enrolled in the original trials, e.g., patients with co-morbid illnesses, patients using concomitant medications, patients with chronic exposure. Many developing countries have rudimentary to non-existent pharmacovigilance infrastructure (e.g., India). Post-surveillance scrutiny of biologics need to be developed. Even in Europe and the US, the introduction of biosimilars (Europe is ahead of the US here) required new rules to be formulated and implemented.

In summary, epoetin biosimilars have created competition in the marketplace and have brought down the cost of anemia treatment. However, their introduction (along with biosimilars of other types of drugs) has provided some lessons: biosmilars are not bio-identical, that they may differ from the innovator molecule in efficacy and potentially adverse effect, and that they require in place a robust pharamacovigilance infrastructure. The US will have epoetin biosimilars on the market within the next 3 to 5 years, that much is certain. 

References

1. Singh A: Gaps in the Quality and Potential Safety of Biosimilar Epoetins in the Developing World: An International Survey. In: American Society of Nephrology: Renal Week; 2006.