Richard Wang, Founder, chairman and CEO of Neukio Biotherapeutics and former CEO of Fosun Kite Biotechnology
Richard Wang is one of the few in China who understands how to develop a cell therapy successfully, as he led Fosun Kite getting the marketing approval from the NMPA for the Chinese version of Yescarta (axicabtagene ciloleucel) this year, the country’s first cell therapy product. He is now ready to move towards “cell therapy 2.0” — allogenic cell therapies from the iPSC-CAR-NK axis.
“I started thinking about what the next exciting thing would be for me. Autologous cell therapy has its challenges in the clinic and the cost is high. I felt I had to do something to make cell therapy accessible to more patients,” he told PharmaDJ.
“Fosun Kite will put a lot of effort to push for commercial success,” he said. “It’s just not as exciting to me as doing innovative R&D work. I’m thinking about how we can overcome the challenges that autologous cell therapies face, and make the next generation of cell therapy for more patients not only with hematological malignancies but solid tumors as well.”
The call for better cell therapy prompted Wang to leave Fosun Kite, and to establish Neukio Biotherapeutics in June this year. Two months later, the startup secured $40 million funding from Lilly Asia Venture, IDG Capital and Sherpa Investments, who share the same vision and support Wang’s plan to build an R&D center and develop allogeneic off-the-shelf immune cell technology platforms.
Within only six months, Neukio has everything set up. The startup opened its R&D laboratory with an area of 1,400 m² in September and put its GMP facility and office into operation this month, concluding the total facility space of 6,000 m². It now has close to 50 employees and plans to double the number in 2022.
“We’re celebrating the completion of our facilities for discovery, translation and CMC,” Wang said, adding the new facility enables the company to do from early discovery all the way to commercial manufacturing.
“The facilities are built for the whole integrated process, meaning that if things work out well, we don’t have to find another place and devote effort to build another facility. We can do all the work here,” he added.
The three challenges
With his experience with Yescarta, Wang understands well what a new product should be like and what bottlenecks need to be addressed early on.
Autologous CAR T cell therapies like Yescarta — using immune cells taken from patients as starting materials — come with high individual variability, so the final product remains inherently different no matter how robust the process is. It also takes weeks from collecting materials to manufacturing and treating the patient. Currently, such cell therapies only work against blood cancer to serve a small group of patients, who can afford the high cost.
Challenges will lie in how to make cell therapy allogenic, ready for scalable manufacturing to reduce costs, and effective in solid tumors to save more lives.
This is where Neukio comes in. “We see iPSC-CAR-NK as a hope for overcoming some, if not all, of these issues,” Wang said.
He explained that using induced pluripotent stem cells (iPSC) comes with a clonal cell bank that promises all vials are the same to reduce the heterogeneity of the patients’ samples. In the stem cell stage, modifications done to clonal cells can be verified at the whole genome level to ensure no off-target editing occurs, thereby reducing clinical risks for patients.
He added that editing autologous or primary cells at the genome level could inactivate some important genes rendering abnormal cell phenotype, and it is hard to rule them out.
“Once correct modification is confirmed, you can pick a clone and build a homogeneous cell bank again,” he said. “From a CMC perspective, using iPSC ensures the genome background is clearly known to go into an established process.”
Meanwhile, using natural killer (NK) cells can avoid attacks on the host to cause GvHD. NK cells also kill tumor cells not by recognizing specific antigens, which Wang sees as a benefit of broad-spectrum cytotoxicity of NK cells. As solid tumors are heterogeneous in nature, it would be harder to use CAR-T to kill all the tumor cells that do not have the same antigen.
“NK cell killing is not dependent on antigen. That’s why it’s possible to use one NK cell product to eradicate broad tumor types even when they are heterogeneous,” Wang explained.
When it comes to manufacturing, taking vials out of the same cell bank is much more convenient and reproducible as an unlimited source of starting materials. He said this enables scalable manufacturing to significantly lower the cost.
To realize these visions, Wang pointed to some specific technical hurdles the approach will face.
For example, the team will need to find out how to differentiate iPSCs into NK cells efficiently to facilitate scalable manufacturing, how to ensure the NK cells infused in patients can avoid quick elimination by the host so they can last long enough to support the desired pharmacokinetics and to overcome the negative suppression by the tumor microenvironment, and how to make cell therapy work against solid tumors.
“We think with the broad cytotoxicity of NK cells, adding a CAR to iPSC-derived NK cells could enhance their specificity. But what particular CAR or antigen to choose to show clinical efficacy in solid tumor will be very critical,” he explained.
How Neukio will address these issues will remain confidential for now. “We have a number of approaches that we think are amenable and feasible to test our hypotheses, and hopefully solve these issues in our products,” Wang said.
Neukio now has the facilities to test out its ideas in the lab to generate data for different indications. The startup hopes to be ready to disclose its pipeline within six to 12 months, and to initiate clinical studies within two years.
Since iPSC-CAR-NK is a very new area and the most advanced programs globally are only in phase I studies, Wang said all products will be innovative and unique. If Neukio is to find licensing opportunities, it will be for technology that can create synergy with its own programs. Currently, it is less likely to get advanced clinical-stage assets.
CMC is key
When pushing Yescarta to the market, Wang worked closely with regulators and different regulatory agencies. This experience helped him understand what clinical and regulatory concerns they had.
Neukio emphasizes CMC from day one, which sets it apart from other competitors. Its team is made up of members with experience in the lab, R&D, quality and manufacturing within the biopharma industry.
“I think most of my competitors have people from the academic world, which is their strength but also their weakness,” Wang said.
“When it comes to developing a medicine, it’s important to understand and meet all the regulatory requirements. At discovery stage, conducting preclinical studies is not only to meet the CDE requirements, but also to generate critical and informative data to help design early clinical trials. I think people worked in industry appreciate this more than the academic people.”
He noted that some competitors carry out preclinical studies at a minimum just because the CDE requires them. They seldom consider how these studies would help set R&D directions and boundaries for future clinical trials. This, in his view, may not help cell therapy development at all.
“We really need to derive clinical hypothesis from our preclinical studies,” Wang warned.
“CMC is so important to hypothesis testing. If the process is not well developed, then we are basically testing different products in different patients. Especially in cell therapy, the process is part of the product. Testing samples manufactured without a sufficiently validated process may mislead people in the clinical data, and many competitors probably still have not realized that.”
He noted that some companies opt not to invest in the manufacturing process until they get good data in investigator-initiated studies in China. Boasting preliminary clinical results stirs sensation and creates quick access to funding, but publicity may not be the right way to develop therapies.
This belief prompted Wang to emphasize CMC early on to ensure Neukio’s product is manufactured consistently and controlled before putting it in the clinic.
He said developing CMC capabilities at Neukio is more challenging than at Fosun Kite, which could just follow an established and validated process to enable a successful tech transfer.
“In Neukio, we don’t have a known, established process. There’s more uncertainly in organizing ourselves and establishing our projects and pipelines especially in the early days,” Wang said.
“If we can overcome the technical hurdles, this will be innovation for the world, as no one has really solved all of them yet. We’re not too late in the game and we still have a chance to lead breakthroughs not just in China but the world,” he added.