Biosimilars in China

Across the globe, many countries have pegged big hopes on biosimilars. The situation is no different in China.  In the face of the supportive pharmaceutical industry policies, China’s biosimilar drug development is riding on an upward trend.

However, compared to the advanced US and European market, China still has plenty of room to catch up. Until now, the FDA has approved nine biosimilars, including seven monoclonal antibodies; the EMA has approved 40 biosimilars, including 14 monoclonal antibodies. So far, no real biosimilar drug has been greenlit in China.

To change this situation, China’s Food and Drug Administration (CFDA) has published a slew of encouraging policies to promote the research and development of biosimilars in China.

In February 2015, CFDA issued the “Technical Guidelines for R&D and Evaluation of Biosimilars (Trail)”, in an attempt to foster the healthy development of the biopharmaceutical industry. This document specified in detail the application procedure, registration requirements and categories for biosimilars.

In July 2016, China released “The Drug Registration Management Regulations (Revised Draft)”, which proposed the implementation of a priority review system and data protection for innovative medications.

Furthermore, on October 8, 2017, the General Office of the CPC Central Committee and the General Office of the State Council jointly published “Opinions on Deepening the Reform of Review and Approval process and Encouraging the Innovation of Drugs and Medical Devices”. Once again, this clearly showed CFDA’s support for biosimilars and its dedication to accelerating the consistency assessment and improving the quality of biosimilars.

Biosimilars have some unique features. The first is their high technical requirements. Because of their production in cells, biosimilars’ effectiveness and safety profile might vary from lot to lot. Thus, the control of quality and critical technologies in the development process is crucial. A number of steps, including cell culture, product processing and purification, storage, etc., all affect the end result down the line. So it comes as no surprise that regulatory agencies, especially in the US and Europe, require a wealth of clinical information and data on biosimilars before approval. This eventually translates into its relatively high production cost.

Adding another wrinkle to this issue, the longer cycle and higher cost of biosimilars also result in a higher investment risk. Generally, it requires 8–10 years, or even longer, to successfully develop a biosimilar, and investment can be as high as $250 million. By contrast, chemical drugs only take 3­­–5 years, and their investment costs range from $2 to 3 million.

At present, the development of biosimilars across the globe is centered around a set of biologics, whose patents have been or are about to expire, including adalimumab, infliximab, etanercept, rituximab, bevacizumab, trastuzumab, etc. The situation is the same in China. In this article, I highlight the research and development of several major biologics in China.

Rituximab

Rituximab, branded as Rituxan, was originally developed by Roche. In 1997 and 1998, it was approved by FDA and EMA respectively. Its main indications are non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis.

Rituximab is a human and mouse chimera monoclonal antibody, which specifically binds to the transmembrane antigen CD20, a widely expressed biomarker on the surface of pre-B and mature B cells. According to statistics, over 95% cancer cells in B cell non-Hodgkin’s lymphoma express CD20. Once Rituximab binds to CD20, it can initiate a series of immune responses, such as ADCC and CDC, eventually lead to the dissolution of B cells.

Currently, rituximab is one of the most effective CD-20 targeted treatments for non-Hodgkin’s lymphoma. When combined with chemotherapy, it is approved as the first-line therapy and has been shown to significantly improve patient’s survival rate. The clinical results have indicated that using rituximab and CHOP chemotherapy together can increase invasive NHL patients’ overall response rate to 83% and their complete remission rate to 76% respectively.

Up to now, the European Union has approved two rituximab biosimilars, including Truxima from Celltrion Healthcare (also marketed as Blitzima, Rituzena, and Ritemvia for different indications) and Rixathon and Riximyo from Sandoz.

On April 21, 2008, Roche’s Rituxan officially entered the Chinese market. Meanwhile, a slew of Chinese biopharma companies are stepping up their game in this race. The most notable is Fosun Pharma. On January 29, 2018, its rituximab injection, with indications in non-Hodgkin's lymphoma and rheumatoid arthritis, was included in the priority review. It is the first China-developed biosimilar to apply for a listing. It is also predicted to become the first China-developed biosimilar to reach the market.  

Following are Innovent Biologics and Sinocelltech. Both of their products have entered Phase III clinical trials. Innovent Biologics’ IBI301 is co-developed with American pharma giant Eli Lily. Its preclinical data has indicated that it is highly similar to Rixutan in all the major characteristics, including primary and higher structures, heterogeneity, biological activity, and process-related impurities. Additionally, its pharmacokinetics and toxicity profile have also been shown to be extremely comparable to that of Rituxan in the preclinical pharmacology studies. Worth mentioning is that IBI-301 received China’s major national special support back in 2014.       

In 2016, the global revenue of Rituxan reached a total of $7.2 billion. Its Chinese market was around $0.16 billion.

Adalimumab

Adalimumab, branded as Humira, is AbbVie’s star product. It has held the crown of best-selling pharmaceutical for several years in a row. Adalimumab was approved by FDA on December 31, 2002 and greenlit by EMA on September 8, 2003. Currently, its main indications are rheumatoid arthritis and ankylosing spondylitis.

Adalimumab is a fully humanized recombinant anti-TNF-α IgG monoclonal antibody. It binds with very high affinities to human TNF-α, thus disrupting the association between cytokines and their receptors. And this series of actions eventually lead to the solubilization of TNF-alpha expressing cells. 

At present, two adalimumab biosimilars have been approved in the US, including Amjevita from Amgen and Cyltezo from Boehringer Ingelheim. Meanwhile, four are approved in the EU; in addition to Amgevita and Cyltezo, Solymbic from Amgen and Imraldi from Samsung Bioepis were also accepted.

On February 26, 2012, Adalimumab made its way into the Chinese market. Currently, almost 20 Chinese pharma companies have their eyes on it. Among them, Innovent Biologics, Bio-Thera Solution, and Henlius are leading the pack.  

On April 7, 2017, Innovent Biologics became the first to enter the Phase III clinical trial in China. Its Adalimumab biosimilar (IBI-303) was shown to be highly equivalent to Humira in a number of characteristics, including pharmaceutical properties, animal PK/PD, and safety profile. In addition, their amino acid sequences, dosage forms, and route of administrations are also identical.

Henlius Biotech, a subsidiary company of Fosun Pharma. On April 29, 2017, it announced that its adalimumab biosimilar was also given the go-ahead for clinical trials in China. However, different from Innovent Biologics, Henlius did not chase the popular ankylosing spondylitis indication. Instead, it went for psoriasis, which was subsequently approved by CFDA for Humira on May 18, 2017.

Having topped the best-selling drug chart from 2012 to 2017, Humira reached its sales peak last year, a total of $18.4 billion. But its performance has not been comparable the Chinese market. Its total revenue in China was mere $31 million in 2016, less than 0.01% of the global market. This is primarily because of its relatively high cost. However, with the Chinese copycats on the horizon, it is predicted that China will see a surge of adalimumab use in China very soon.

Infliximab

Infliximab is another popular anti-TNFα monoclonal antibody. It was developed by Janssen, branded as Remicade, and approved by FDA and EMA in August of 1998 and 1999, respectively. Currently, it is primarily used to treat inflammation-related diseases, including Chron’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

Infliximab is a humanized mouse anti-TNFα monoclonal antibody. It binds with the soluble and transmembrane form of TNFα with very high affinities, inhibiting their association with the receptors. This eventually leads to the loss of function of TNFα, exerting its anti-inflammatory effects.

So far, only two infliximab biosimilars have been approved in the US. They are infliximab-dyyb, branded as Inflectra, from Pfizer and Celltrion and Ixifi (infliximab-qbtx) from Pfizer. On the other side of the coin, EMA has greenlit three, including Inflectra from Pfizer, Remsima from Celltrion, and Flixabi from Samsung.

On May 17, 2017, Remicade was officially approved by CFDA. Its biosimilar research and development in China has been catching up since then. Biomabs and Hisun Pharm are leading the race. Worth mentioning is that with a CFDA nod for production in hands, Biomabs’ development is the fastest. Its infliximab is produced in CHO cells and has been tested to have good clinical results and low immunogenicity.

In 2017, the global revenue of Remicade reached a total of $7.15 billion. Its sales in China are not currently clear. But if we look at the most recent available data (2015), China only represented about 0.6% of its total market share - $50 million.

Etanercept

Etanercept is a fusion protein of recombinant human TNF-α receptor and human IgG-Fc. It was first developed by Amgen and subsequently approved by the FDA and EMA in November 1998 and February 2000, respectively.

Etanercept can competitively block the binding between TNF-α and its cell surface receptor, thereby restricting the excess TNF- α in the body and inhibiting the induced abnormal immune response and inflammatory process. It is mainly used for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, and forced spondylitis.

Currently, FDA has only greenlit Erelzi from Sandoz; whereas, the EMA has approved both Erelzi and Benepali from Samsung.

Etanercept jumped into the Chinese market on February 26, 2010, which was relatively late compared to other biologics in this list. However, its Chinese copycats actually appeared quite early. CP Guojian Pharm was the first to get an approval; its version made it to the market in 2005. Celgen Biopharma and Hisun Pharm were the second and third to the market, receiving a nod in 2011 and 2015 respectively. Worth noting is that these copycats are not true meaning biosimilars, due to their structural differences and the lack of head to head clinical trials.

Trastuzumab

Trastuzumab, originally developed by Roche’s Genentech, is currently branded as Herceptin. It was first approved by FDA and the EMA in September 1998 and in August 2000, respectively.

It is an anti-HER2 monoclonal antibody. By attaching to HER2, it can block the binding of human epidermal growth factor to HER2, leading to the reduction of cancer cell growth. Currently, its main indications include breast cancer, metastatic gastric cancer, and metastatic esophageal and gastric junction cancer with overexpressing HER2.

So far, only two trastuzumab biosimilars have made their way into the market. They are Ogivri, by Mylan and Biocon, approved by FDA and Ontruzant, from Samsung Bioepis, approved by EMA.

Trastuzumab was approved by CFDA on September 5, 2002. At present, a slew of Chinese pharmas are gearing up to become the first to bring a domestic version to the market, including Fosun Pharma, Genor Biopharma, and Anke biotechnology. All have entered the Phase III clinical studies.

With a total of $7.441 billion sales in 2017, Herceptin made the fifth position in the top 15 best selling drugs in the world last year. At the same time, it is the number 2 top selling anti-tumor medications in China, with $159 million revenue in 2016, representing about 2.8% of its global market.

Bevacizumab

Bevacizumab, branded as Avastin, is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), developed by Roche. It was approved by the FDA and EMA on 26 February 2004 and 12 January 2005, respectively.

Through inhibiting tumor angiogenesis, it intervenes the tumor nutrition supply, thus starving the tumor growth. Currently, the applications include metastatic colorectal cancer, non-small cell lung cancer, and other metastatic cancers.

Up to now, there is only one biosimilar in the market, Mvasi (bevacizumab-awwb), co-developed by Amgen and Allergan, listed in both the US and EU. 

Avastin entered the Chinese market on February 26, 2010. Right now, Qilu Pharmaceutical and Innovent Biologics are at the forefront of the Bevacizumab biosimilar development; both are undergoing Phase III clinical trials. Fosun Pharma is in the second tier, with one product in Phase I clinical testing.

In 2017, the total revenue of Avastin was $7.096 billion globally. With $70 million sales in China, it was the fourth most popular anti-tumor medication in 2016.

The future of Chinese biosimilar development

In the face of more talent returning from overseas, China’s biologics research and development is maturing rapidly. Meanwhile, a host of supportive policies from CFDA is further driving China’s domestic biosimilar development forward.

However, the path ahead is not all rosy; Chinese productions will certainly face a range of new challenges in the future.

The first burning question on the mind of Chinese pharma bosses concerns pricing and promotion strategies. Different from chemical generics, the price cut for biosimilars will not be very large. Thus, how to promote and price becomes a critical issue in the biologics market.

Another prevailing question is how to compete with the original and strive to be included in national healthcare insurance. This is very important, especially in the light of CFDA’s new policy. On April12,  2018, China issued a zero tariff on imported anti-cancer medications, in an attempt to further advance China’s healthcare system, particularly in late-stage and hard-to-treat cancer field. Foreseeably, this might lead to more fierce rebates from the foreign originals, affecting the market potential of China-developed biosimilars down the line. 

Jin Zhang M.D., Ph.D is project and account manager at LakePharma, and editor at The Pharmaceutical Consultant.