Xuzhou Medical University

Need to Know: To understand the evolution of the global CAR-T space, a Pharmaceutical Technology analysis paired drug and clinical trial data with the time CAR-T therapies were first identified as being in development by GlobalData. The data shows that specialist biotechs in China are building a heavy pipeline of CAR-T therapies, and for each CAR-T therapy developed by US companies, there are 1.5 CAR-T therapies being investigated by Chinese companies. While the pandemic and China’s ‘Zero Covid’ policy has impacted CAR-T trials, experts in the field point to increased investments towards scientific and manufacturing infrastructure as key in driving this expansion In August 2017, Novartis’s Kymriah (tisagenlecleucel) broke ground by becoming the first chimeric antigen receptor (CAR) T-cell therapy in the world to bag an approval to treat acute lymphoblastic leukemia (ALL) patients in the US, followed closely by Gilead Sciences’s Yescarta (axicabtagene ciloleucel). Both therapies were later approved in Europe, the next year. That the initial approvals happened in the US was emblematic of how CAR-T development was centered primarily in the West, and more specifically the US, in the mid-2010s. Between 2010 and 2014, over half of newly identified CAR-T therapies were being developed or co-developed by a US-based company. In 2021, however, that figure has fallen to less than one-third of new drugs. The reason for this is not a drop-off in American focus on CAR-T therapies, but instead a sharp increase in new CAR-Ts being developed by Chinese companies. The development of CAR-T therapies in China appears to markedly outpace research happening in the West, as per an analysis by Pharmaceutical Technology. CAR-T drugs now account for over 10% of new drugs developed by Chinese companies, compared to only 2% of drugs developed by US companies. Moreover, for each CAR-T therapy developed by US companies, there are 1.5 CAR-T therapies being investigated by Chinese companies. To understand how the CAR-T development sector has evolved since 2010, we paired drug and clinical trial data with information on the time CAR-T therapies were first identified as being in development by GlobalData. Global Data – the parent company of Pharmaceutical Technology – tracks press releases, clinical registry protocols and research papers to identify new drugs. Even as the Covid-19 pandemic slowed pharmaceutical research across the world, data shows that Chinese companies are still developing more CAR-T therapies than American entities. Slow but steady There are several unique factors driving this surge in CAR-T developments in China: the need and demand for such therapies, government support, capital flow, and Chinese scientist-driven local research, says CAR-T investigator Dr Peihua (Peggy) Lu. CAR-Ts are a complex type of cell therapy, where immune T cells are engineered to express chimeric antigen receptor (CAR) that binds to certain proteins on the tumor cells. Compared to other types of drugs, CAR-Ts require strict manufacturing and administration adherence, which made their development resource-intensive and expensive. As such, their development in different parts of the world was stymied by the need to make large upfront investments in R&D, manufacturing, and scientific expertise to build a CAR-T-friendly ecosystem. Once the initial foundation was laid, data indicates that China sped ahead to employ this therapeutic approach. Between 2010 and 2014, GlobalData identified around 90 CAR-Ts in development, and in 2021 that number increased to over 300. As part of Healthy China 2030 and other pharma and healthcare visionary programs, the country enhanced its focus on innovative therapies, says Sasmitha Sahu, a pharma analyst at GlobalData. There has been an influx of investments recently as illustrated by the fact that from 2018–21, domestic Chinese cell therapy companies have raised approximately $2.4 billion, says Lu, who is also medical executive president at Lu Daopei Hospital in Beijing. David Deere, an operational pharma consultant with expertise in China’s reimbursement landscape, also points to the ‘Made in China 2025’ policy—a 10-year national strategic plan to develop the manufacturing sector, as key to this domestic-focused approach to developing therapies. Healthcare in addition to other sectors has received significant investments in this regard, he says. On average, the number of newly identified CAR-T therapies from Chinese developers has doubled every year since 2014. Deere says the scale of CAR-T-related investigations is unsurprising. “It takes a village to do a CAR-T trial and large hospitals have their own experienced team with investigators and nurses who are eager to participate and open such studies, which has accelerated this research,” says Lu. In China, Deere says, large first-tier hospitals are a world and governments unto themselves, and CAR-T development in that kind of an environment is ideal. “CAR-Ts require such a personalised and intellectually sophisticated approach, so you can see why your retired physicians and scientists would gravitate towards something like that, which is why this area has exploded in the country.” This research landscape, which “sea turtles,” or Chinese scientists who have returned to the country after training abroad, are spearheading, is another contributing factor to the growth of specialised research. Several years ago, the Chinese government made a conscious effort to develop CAR-T locally and invested a lot of money and resources in setting up hospitals and infrastructure, which is critical for this kind of research, says Dr Samir Parekh, director of Translational Research in Myeloma at The Mount Sinai Hospital, New York. While the development of most CAR-Ts is led by commercial companies in both the US and China, both have universities and hospitals that have been regularly involved in CAR-T development. For China, these are the Shenzhen Geno-Immune Medical Institute, Xuzhou Medical University, and Zhejiang University. Even if a US academic center makes a CAR-T, which can cost over $100,000, not all have GMP manufacturing facilities to then manufacture them on a wide scale, says Parekh. It’s not easy to make a homegrown CAR-T, unless you have a big funding source, he adds. Domestic vs. international pharma China’s race for domination in this field means that of the 10 companies involved in the development of the most CAR-T drugs since 2010, six are based in China. Considering the initial approval, unsurprisingly, Novartis is one of the two biggest developers of CAR-T therapies—the other being Bristol Myers Squibb. Between 2014 and 2016, GlobalData identified 18 new drugs being developed by one of the two companies, equal to 10% of all new CAR-T therapies during the period. Each company’s rate of new CAR-T development has slowed in recent years—collectively they were responsible for just 1% of new drugs identified since 2019. In China, on the other hand, CAR-T research is undertaken by specialist biotechs. For the 10 biggest developers of CAR-T therapies in China, over 80% of their developed drugs since 2010 are CAR-T therapies. China's top CAR-T developers are newer and more specialised than the West's Newly-identified drugs developed by each region's top 10 CAR-T developers Source: GlobalData Parekh, who was involved in one of the trials that led to Carvykti’s approval in the US, says the initial impressive efficacy data with Carvykti from China has been instructive for ongoing studies in the US that are now exploring it in earlier lines of treatment. Even though China has more CAR-Ts in the pipeline, thus far the country’s regulatory agency, the National Medical Products Administration (NMPA), has approved only two CAR-T therapies: Gilead’s Yescarta, which was co-developed with FosunKite for the China market, and JW Therapeutics’s relmacabtagene autoleucel injection or relma-cel, which became the second approved therapy in September 2021. Even though the two NMPA-approved CAR-T therapies are not yet covered by major insurance in China, a couple of hundred patients have already received these drugs through private funding or outcome-based reimbursement schemes with the individual company, Lu says. Relma-cel is an indigenously produced CAR-T and is likely to be included in the next National Reimbursement Drug List (NRDL) update since indigenous therapies were favoured over drugs from international companies, says Sahu. Particularly in the case of CAR-Ts, which are personalised therapies, Deere says it would be difficult “for multinational companies to compete with domestic Chinese companies, not only because of the cultural and linguistic factors”, but also because the government is going to likely prefer national companies. CAR-T focus evolves Current research trends validate the research interests and wins in the CAR-T field in the last 10 years. While initial CAR-T therapies were personalised autologous therapies directed toward the CD19 antigen in relatively rare blood cancers, subsequent development has branched out to allogeneic or off-the-shelf therapies in several cancer types. In line with the initial approvals, in both the US and China, the most common indication for which CAR-T drugs have been developed is a blood cancer. In fact, 60% of CAR-T drugs developed by Chinese companies and 55% of US CAR-T drugs have blood cancer as a listed indication. CAR-T therapies need a target antigen that is ubiquitously, and ideally exclusively, expressed in a tumor, which is the case with hematological cancers. As such, developing this modality in solid tumors has been and continues to be challenging. Still, since the initial successes in ALL and B cell lymphomas, the focus on CAR-T therapies in the US is slowly shifting towards solid tumors, with 21% of the CAR-T therapies being designed against solid tumors. In China, however, this does not appear to be the case yet, with only 9% of all CAR-Ts being developed in solid tumors. One potential reason for the drop in CAR-T research can also be attributed to the rise of effective bispecific antibodies. Often looked at as “poor man’s CAR-Ts,” Parekh says these offer an off-the-shelf alternative that can compete with CAR-Ts and potentially even leapfrog them. So far, efficacy signals have been encouraging, and these antibodies could also be used more easily in smaller community hospitals, he adds. Research continues despite the pandemic Despite the disruptive impact of Covid-19 on trials worldwide, trials, in general, have continued in China, and this is the case with CAR-T therapies as well. Dr Lu says her hospital recruited 272 patients in different CAR-T trials in 2019, which increased to 329 patients in 2020, and 394 patients last year. Participating in a trial also allows patients to access expensive CAR-Ts without having to pay from their pockets, which in addition to the encouraging efficacy results in certain cancers has incentivized participation. In the US, while things are now picking up, Parekh says a lot of academic centers are facing shortages of skilled researchers following the pandemic. Recent lockdown restrictions in line with China’s ‘Zero Covid’ policy has made trial site visits difficult at times. But Lu says that since lockdown policies usually last for a few days to a month and are specific to a particular location only. Moreover, preclinical CAR-T research has continued during this time. Given the results seen with CAR-T therapies, especially in cases where it’s a life-or-death situation, patients are willing to make every effort to join a clinical trial, says Lu. Cell & Gene Therapy coverage on Clinical Trials Arena is supported by Cytiva. 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