Can China Ace The CAR-T Race?
Executive Summary
Helped by Nanjing Legend's multimillion dollar deal with J&J, China has now overtaken the US in number of clinical trials using CAR-T cell approaches to treating cancers, but could uncertainties derail the country's CAR-T train from steaming ahead?
Armed with deals from a variety of multinationals and a flurry of domestic development activity, China is poised to become a major force in treating cancers using the latest CAR-T technology.
Already, the country has the highest number of ongoing CAR-T clinical studies in the world, overtaking the US by a large margin. Per data from Informa's Trialtrove, there are now a total of 237 CAR-T trials registered in China, compared to 186 in the US.
Since the US FDA approved the first CAR-T therapy, Novartis AG's Kymriah (tisagenlecleucel) for B-cell acute lymphoma last August, and later Kite Pharma Inc.'s Yescarta (axicabtagene ciloleucel) for adult large B-cell lymphoma, the global race to commercialize CAR-T therapies has begun.
Not surprisingly, nearly half, or 106, of the Chinese CAR-T trials are for acute lymphoma, closely followed by Hodgkin's lymphoma (101) and chronic lymphoma leukemia (54).
So far, several domestic biotechs have obtained clinical trial approvals for their CAR-T therapies, including Nanjing Legend with LCAR-B38M. Legend took last year's ASCO meeting by storm by announcing promising clinical results for the product, and in December Johnson & Johnson agreed to pay $350m upfront to develop the product, initially for multiple myeloma with B-cell maturation antigen.
Time To Clinic Reducing
Not only the sheer number of trials, but also reductions in the time needed to get to the clinical study stage, are seemingly fueling China's drive to become a major global player in the field.
It now takes a relatively shorter time for domestic developers to take projects into the clinic thanks to a government policy to encourage cutting-edge innovation, especially when it comes to treating cancers. China has high incidence rates of certain prevalent cancer types including lung, liver and colorectal, while others such as thyroid, pancreatic and prostate are increasing.
Unlike in the US, where five-year survival rates are steadily improving, China has seen slow progress in post-surgery, five-year survival figures, adding to the drive for new therapies.
In a bid to encourage the earlier introduction of CAR-T drugs to the market, the China FDA on March 16 released its first Cell Therapy Clinical Study and Review Guidelines, paving the pathway for the regulator to review and approve such products as a "living" therapy.
The rules urge developers to carefully consider pharmacology and data dossier preparations. For instance, applicants need to explain whether CAR-T cell cultures contain serum or other animal or human products, and companies also need to follow previous CFDA guidance on cell therapy Study and Review Technical Principles.
Starting Out
But the competitive landscape for emerging therapies is becoming more complicated, pointed out industry experts attending a recent Life Sciences Forum held in Mashan, Wuxi on April 21-22.
"CAR-T has better targets but it lacks variety, so developing combination therapies is becoming trendy," said Sun Wenjun, VP and head of Government Affairs at WuXi Juno, a joint venture devoted to developing innovative cell therapies set up between WuXi AppTec Inc. and Juno Therapeutics Inc..
The issues facing Chinese CAR-T developers lie in several aspects, including cell manufacturing and selection, cost considerations, and safety profile. Because of a cell's complexity when multiplying inside the body, it is essential to ensure the quality of engineered T-cells - only young and thus stronger cells can ensure persistence of efficacy, noted the expert.
To that end, dosing should be carefully weighed as to whether a fixed dose or flexible dosing based on the tumor type would be better.
Additionally, safety profile has been a major issue for many CAR-T therapies. Cytokine release syndrome is a common and potentially dangerous complication of anti-T cell approaches, and Juno for its part was forced to halt trials for its lead asset JCAR015 and refocus on JCAR017. (Also see "Juno Ends JCAR015 Development In ALL, Cementing Third Place CAR-T Position" - Scrip, 1 Mar, 2017.)
How Chinese biotechs might mitigate the potential adverse events with their candidates over marketed and other CAR-Ts will likely decide their fate.
Cost Considerations
Meanwhile, they must also consider the cost and time to market. Novartis's Kymriah, priced at $475,000 in the US, will be beyond the reach of most Chinese cancer patients without medical insurance coverage. The high cost may partially explain that in the first quarter of 2018, Novartis reported only $1.2m sales of the drug, a relatively low figure for the first approved CAR-T treatment.
Facing high diagnostic fees associated with the new therapies, Chinese developers must also consider end cost along with time spent during the clinical development and regulatory process. While front runner Nanjing Legend has a lead advantage, others must differentiate, in indications including solid tumors, noted Lu Jinwei, head of CAR-T at Eureka Therapeutics Inc., a China-US hybrid biotech.
"Having a cutting-edge technology may not lead to cutting-edge production and product," he said.
From the editors of PharmAsia News.