As the regulatory frameworks for biosimilar development are evolving in both US and EU, more and more biosimilar developers are entering the competitive landscape. Many commercially successful Oncology biologics are going off-patent in next few years, presenting a lucrative opportunity for biosimilar development. The biosimilars pertaining to these biologics constitute the first wave of mAb biosimilars – Avastin®, Herceptin®, and Rituxan®/MabThera®. These 3 Oncology products have a cumulative global sale of over USD 18 billion , constituting over 21% market share of the total Oncology sales in 2015 (global Oncology sales USD 83 billion) .
Erbitux® (cetuximab) marketed by Lilly and Merck is the fourth Oncology product in the first wave of mAb biosimilars. Despite the loss of expiry of the key composition of matter patent for cetuximab, in both US and EU, there is no biosimilar interest for the product. This signifies that the reference biologic´s market value is a key (and perhaps the only) driver for biosimilar portfolio management decisions.
The Oncology biosimilar development requires a case-by-case approach depending upon the reference biologic´s structure, tumor biology, mechanism of action, and target patient population. Let us discuss the key oncology biosimilars in detail.
Bevacizumab: Avastin® was first launched in 2004 . It is a commercially successful product with global sales of over USD 6.8 billion in 2015 . The sales of Avastin® are not expected to decline and it will continue to be one of the top selling biologic at USD 6 billion by 2020. Avastin® is approved in multiple in the following indications :
Avastin® is a highly attractive reference product for biosimilar developers, driven by it commercial success, breadth of its label and the absence of any next-generation therapy (from the originator, Roche). Roche continues to expand Avastin´s label both as monotherapy and in combination with other pharmacological agents e.g. in 2016, Avastin® in combination with Tarceva® was approved for first-line treatment of patients with EGFRm+ NSCLC patients .
The choice of indication for pivotal Phase 3 non-inferiority study for proposed bevacizumab biosimilars, is NSCLC. This choice is driven by the regulatory requirement of a “sensitive” patient population, additionally supported by the high incidence of disease. Amgen is leading the competition at present, and has filed for approval of its proposed bevacizumab biosimilar – ABP-215 in both US and EU [5,6]. The company presented Phase 3 clinical readout in the ASCO 2016 (Abstract #9095) . Pfizer, Merck/Samsung and Boehringer Ingelheim are next in line with several others following closely including Centus Biotherapeutics (JV of AstraZeneca and Fujifilm Kyowa Kirin Biologics, based out of UK), Oncobiologics, Sandoz, Mylan and others. The clinical program of each competitor is a single trial with close to about 680 (± 10%) patients in each with no marked differences in the trial design.
Trastuzumab: Herceptin® was first launched in 1998 . It is a commercially successful product marketed by Roche. The global sales for Herceptin® were USD 6.8 billion in 2016  and are expected to decline by 5-10% in next 5 years. The key patent for Herceptin® has already expired (July 2014) in EU and will expire in June 2019 in US. It is approved for the following indications :
The biosimilar clinical programs for trastuzumab shows significant diversity. Biosimilar developers have adopted different interpretations for the “sensitive” patient population and subsequently set up different registration trials. For example, Mylan has already filed for approval of its proposed trastuzumab (MYL-1401O) biosimilar with FDA  & EMA , based on a Phase 3 non-inferiority study in treatment naïve HER2+ metastatic breast cancer population . Celltrion on the other hand, has also filed its CT-P6 for EMA with clinical evidence in metastatic HER2+ breast cancer and adjuvant HER2+ breast cancer patient populations . Pfizer has two ongoing Phase 3 clinical studies – 1st line metastatic and early breast cancer patients. Amgen, Samsung/Merck & Co., have chosen to conduct single Phase 3 trial in early HER2+ breast cancer patients.
The regulators from US and EU have been emphasizing that each biosimilar application will be reviewed on a case by case basis. Mylan’s trastuzumab application will set an important precedent in this regard. It will be critical in understanding the “sensitive” patient population for clinical study design and the case by case treatment of applications by the regulators. Mylan’s EU application is pending review, while the FDA’s Oncologic Drugs Advisory Committee (ODAC) has recommended MYL-1401O for approval. A final decision by FDA is pending first week of September.
Rituximab: Rituxan® is a chimeric monoclonal antibody against the protein CD20 . It was first approved by FDA in November 1997 (marketed as Rituxan® by Roche) and by EMA in June 1998 (marketed as MabThera® by Roche). It is commercially successful product with annual sales in Oncology over USD 5.8 billion in 2016 . Rituxan® sales are forecasted to drop by 10% in the next 5 years. Rituxan® is indicated for (in cancers) 
Additionally, rituximab is also indicated for Rheumatoid Arthritis, Granulomatosis with Polyangiitis (Wegener’s Granulomatosis) and Microscopic Polyangiitis. Indication extrapolation between Oncology indication and Immunology indication is not possible therefore, biosimilar development ongoing in both follicular lymphoma (Oncology) and rheumatoid arthritis (Immunology) indications. Sandoz, Pfizer, and Amgen have advanced clinical programs followed closely by Celltrion
The clinical development landscape, for rituximab biosimilars in Oncology, is centered around Follicular Lymphoma. The study design for each biosimilar product varies with respect to the patient enrollment and trial sites. Celltrion is leading the pack, having filed its biosimilar Truxima® with FDA and secured an approval in EU . Amgen, Sandoz, Pfizer, and others are following closely.
Biosimilars is a high-risk, high-gain opportunity and needs a certain commitment for the long haul. The current set of biosimilar developers have already made the necessary investments in terms of fixed costs (manufacturing and product development technologies) and have incurred expenses towards the ongoing clinical development, which constitutes a major part of the variable cost (marketing and promotional spends would be another component of the variables costs). The figure below shows clinical spends towards the first wave of Oncology biosimilar assets of key companies as of July’16.
The clinical spend analysis not only indicates the sunk costs towards clinical development of the biosimilar assets but also serves as a proxy for a company’s commitment towards biosimilars. In addition to the clinical study expenses, biosimilar marketing and commercialization also requires high investment, due to nascent nature of this space. The competitors will have to build enangement with all key stakeholders including prescribers, payers and patients.
In the part three of this five part series, we will explore how companies are actively engaging with stakeholders and shaping the biosimilar space to their advantage.