The first therapeutic antibody was approved by the FDA in 1986; thirty years later, there are over 70 approved monoclonal antibodies, and hundreds currently in clinical trials. China has been a relative latecomer to this field but is advancing rapidly.
In March 2018, the FDA approved the first antibody originating in China: ibalizumab-uiyk (Trogarzo), for treatment-resistant HIV infection. Thirteen other biologics developed in China are currently in clinical trials.
The state of antibody development in China, and its future, were the topic of the day at the second annual meeting of the Chinese Antibody Society, which recently took place in Cambridge, MA. This two-year-old organization has more than 1,200 members, with more than half of its members in the U.S. Its mission includes acceleration of FDA approval and marketing of antibody-based therapeutics that have been developed in China. At the meeting, the Society announced the launch of a new journal, Antibody Therapeutics.
Managing Financial Risk
Chinese companies have mainly focused on developing treatments for validated targets as a way to manage financial risk. These include developing new chimeric antigen receptor T cells (CAR-T), which have emerged as potential leaders in the antibody field. The CAR replaces the function of a T-cell receptor with an antibody that reacts with a target on the surface of the cancer cell. Bill Stroh, Ph.D., founder, BiStro Biotech Consulting, notes that “about half of the CAR-Ts in clinical trials are sourced in China. This is very innovative work.”
But a central problem with CAR-Ts is that “by and large, you are dealing with a relatively uncontrolled situation. Proliferation and expansion varies from person to person, and the type of T cell coming out is very uncontrolled. Only when we get a highly predictable situation will we be able to treat tumors with T cells.” notes Dr. Stroll.
There are over 900 biologics currently in clinical trials, mostly antibodies and mostly focused on oncology. Immunology takes second place. “We are now in the biologics era. But in the next ten years, we will be handing it off to the gene therapy era, so enjoy it while you can,” Dr. Strohl says.
Targeting Cancer
Most companies developing therapeutic antibodies are targeting cancer, and companies in China are no exception. Michael Yu, CEO of Innovent Biologics said that, by his estimate, China is about five years behind the global competition in development of antibodies for PD-1, PD-L1, and other targets, as well as for development of CAR-Ts for CD19, the most popular cancer cell targets.
Initially China led the field of oncolytic viruses, he says, but is now behind. “China is catching up, but there still is not much true innovation in the immuno-oncology space, compared to the U.S. and other areas of the world,” he continues. The number of Chinese companies developing immunotherapies for cancer continues grown steadily, from only a handful in 2000 to over 90 today.
Innovent Biologics has seven products in the pipeline, including IBI322, a bispecific antibody against both CD47 and PD-L1, which Yu says has a superior toxicity profile to current PD-1 based therapies nivolumab (Keytruda) and pembrolizumab (Opdivo), based on data released at the 2018 ASCO meeting.
Further, he says, the price of IBI322 “will be dramatically reduced compared to nivolumab and pembrolizumab,” at least for the domestic Chinese market. “The majority of Chinese are not able to afford these [other] medications.”
Cheng Liu, CEO at Eureka Therapeutics, presented his company’s strategy of using CAR-Ts to target intracellular cancer targets, using fully humanized antibodies that recognize surface antigens derived from those targets and presented by the MHC complex. The potential of the strategy, he says, derives from the fact that 90% of cancer targets are intracellular proteins, “inaccessible by small molecules or other antibody-based drugs.” The challenge is that MHC expression on cancer cells is highly reduced, with only several hundred complexes, versus 60,000 on a normal cell, he adds.
One CAR-T in their pipeline targets alpha-fetoprotein, which is not expressed by normal cells but is by cancer cells, including liver cancer. Liver cancer is one of the most common causes of cancer death worldwide, with one million new cases each year, with half of those in China. Their lead compound, ET1402L1, is currently in early clinical trials.
Yongjiang Hei, CMO of Qilu Pharmaceuticals, spoke of the challenges and promise of antibody-drug conjugates (ADC). An ADC has three components: an antibody that binds to a surface molecule on the target cell, a chemotherapy drug, and a linker than binds drug to antibody. In principle, he says, ADCs offer major advantages over antibodies alone, since the surface antigen they bind to doesn’t need to be pathogenically relevant—anything that brings the drug within close proximity of the tumor cell will do.
However, there has been a very high failure rate in ADC development, stemming from the inherent complexity of working with three different entities. “Every single component is important, and when you include all three into one molecule, they all have to work together,” Hei says. The linker chemistry in particular is very complex, since it must prevent premature release of the drug to reduce toxicity, but then release it efficiently at the target to promote efficacy.
Regarding the pace of drug development in China, Hei points out that “research and development in the industry is relatively new, and there is not a history of infrastructure or culture that has supported strong R&D. There are very few companies that have the experience of taking one molecule from the beginning to the end.” One reason antibody development has surged ahead of small-molecule drug development is that companies don’t need the huge compound libraries, or the many years it takes to develop them, for antibody research.
In addition, Hei notes, the financial incentives for innovation are less attractive, since drug prices in China are low, and the most expensive drugs are not reimbursed, limiting their market. “The mechanism of reward is not there.”
Scott Liu, President and CEO at Henlius Biopharmaceuticals, a company that makes biosimilars for both Chinese and international markets, says, “There is a huge unmet need in China. There are over one billion people who can't afford or don’t have access to imported biologic drugs.”
While the price of imported biologics is often less than the same drug in the U.S., they nonetheless represent a much greater percentage of annual income. Furthermore, the population is aging, and prevalence of many diseases, including cancers, are increasing due to environmental pollution. “China has 37% of the world’s lung cancer patients,” says Liu.
“The good news is that the biosimilar market is booming,” with a surge of venture capital into the healthcare sector, as well as important regulatory innovations. One of these allows biosimilars to use the same generic name as the original drug. “This is quite important, since insurance coverage is based on the generic name” as given on the national health insurance list, Liu says. In addition, the rate of regulatory review and approval has accelerated.
Most Chinese companies making biosimilars “do not meet international quality standards for their manufacturing operations and very few companies have the talents and resources to develop and market their products globally,” says Liu. Henlius has bucked that trend, developing oncology biosimilar therapeutics, including biosimilars of rituximab, trastuzumab, and others, for both Chinese markets and internationally in Mexico, South America, Russia, and other countries.
A major hindrance to development of the Chinese pharmaceutical industry is the limited pool of top talent, Liu says. “It’s difficult to find experienced people who are willing to go back, to return to China after education and experience abroad. That’s the biggest challenge. On the other hand, the career opportunities are tremendous. In the U.S., very few principal scientists can become a director or vice president.” But if such a scientist returns to China to take a position, “the pay scale can be higher, there may be stock options, and their status can be higher. If you are a manager in the U.S. in Big Pharma, you can easily become a director or even a VP in China,” Liu adds.