Editor’s note:

On January 15, 2023, Luye Pharma Group announced that the U.S. Food and Drug Administration (FDA) has approved Rykindo® (risperidone) for extended-release injectable suspension. This is the first new drug independently developed by Chinese pharmaceutical company in CNS area that received approval from U.S. FDA. It is also the first complex preparation product developed by a mainland Chinese pharmaceutical company to receive FDA approval under 505 (b) (2) pathway. The approval represents a historic breakthrough made by a Chinese company. The success of this project can’t live without efforts and contributions of many Luye colleagues for the past 11 years. This month we are honored to invite 3 colleagues from this project to share the past, present and future of Rykindo.

From left to right: Dong Ying, Senior Director of International Clinical Development; Shi Yanan, Project Manager of LY03004; Paul Buckley, Vice President of International BD

Q: Congratulations on the approval of Rykindo in the U.S., and thank you all for taking this interview to share your stories. To start with, can you give us a brief introduction of yourself?

P: I’m Paul Buckley. I joined Luye in 2016 as Vice President of Corporate and Business Development. During that year, Luye started to expand its business beyond China and made the first deal of an international business--Acino. I have been involved with all the M & A business development and commercial activities from then on including the acquisition of Seroquel from AstraZeneca. Before I came to Luye, I have worked at companies including Merck, Wyeth, Pfizer, Perrigo and others covering areas of engineering, manufacturing, business development and corporate development through most of my career.

Speaking of my involvement with this project, it actually started in 2018. We worked with a consulting company to develop a detailed forecast for Rykindo, and also to understand high-level positioning for the product to come up with a preliminary go-to-market strategy and detailed project plan. Then we started to build up a commercial team for Rykindo in 2019. However, the launch preparation was delayed due to the first CRL from FDA. And now it brings us up to today where we got approval in January, and we have to prepare for accelerated launch of this product.

Shi: My name is Shi Yanan. I have been working on drug delivery system research since my PhD in 2013. I joined Luye Pharma R & D center in March 2015 and immediately joined LY03004 project. I started from drafting preparation development reports, and then I was responsible from preparing CMC documents for NDA, IMPD, PAI inspection and coordination. Now I’m the PM of this project.

Dong: My name is Dong Ying, I joined Luye in September 2017 and now serve as the Senior Director of International Clinical Development. Before joining Luye, I have also worked for Eisai, Deciphera and other pharma companies. I joined LY03004 shortly after I joined Luye, responsible for clinical documents and label writing. During the two subsequent re-submissions, I worked closely with the China team as the head of the international clinical team and successfully completed the filing tasks, and had the honor to witness the launch of LY03004 as the first self-developed product of Luye Pharma in the U.S.

Q: The approval of Rykindo is a great news for everyone, how did you feel about this at first? What is the significance of this approval?

Dong: The moment that I received the news, I felt a bit like the moment of relief after giving birth. Since it was already Friday evening in the Eastern United States, I only sent a text message to colleagues who were still waiting for news: "Approved!" Sleepless is the only word that can describe how I felt. The approval of Rykindo in the U.S. is not only a historical milestone to Luye, but also the entire Chinese pharmaceutical industry. It shows our strength in CNS, which also boosts the morale of our team in oversea markets. We have learned that we can only succeed if we don't give up, because the approval of Rykindo is a daunting journey in the past 11 years. The China team and international team work together with perseverance, carefully and thoroughly analyzing the requirements of the FDA during each submission, searching for the most reasonable answers, and rigorously and meticulously analyzing the data to ensure that the most satisfactory answers are given, which also makes us deeply aware that only with a united effort can we be invincible.

Shi: Yes, we were waiting for the news for the whole night. Our colleagues were still communicating with FDA till 4 o’ clock. When I received the news, it was already 6 in the morning. I was so excited and jumped from my seat. This project is like our own child; I can’t remember how many late nights we have worked for this project. We faced many doubts and challenges during these years, but we never gave up. Now it is our moment to proudly say: “The first complex preparation is developed by us—Luye Pharma”. No matter how many obstacles on the way, as long as we stick to it, finally we will get to the destination. We have all learned and developed ourselves during this process, and I’m more confident to handle more projects in the future.

P: I was a little surprised by the approval at first and then excited. The first CRL was legitimate to our issues. We had to go back and address those issues. And the second CRL was in the middle of COVID crisis and FDA was not in a rush. But the good thing is the long acting injectable market has grown and the generics hadn't made it to the market, which was our biggest fear. 

For Luye, the approval is extremely strategic because it now shows to the world that we have the capability and technology to get a complex product approved. This is not an easy, oral solid dosage. This is a complex product that Luye received approval in the U.S. It is a major strategic accomplishment for the organization. It means Luye is now competing on the international scale. It took us over a decade to achieve this goal, but now going forward from this point, we have the confidence that we know how to do it and our future pipeline will get approved, because we've been through all this. Our next task is to commercialize this product, I’m looking forward to moving forward with this product and making it not only a strategic success but also a commercial success.

Q: You are responsible for global clinical development of different projects in oversea countries, as the responsible person of this project in the U.S., what is the biggest difference and challenge of LY03004 compared with other projects?

Dong: Compare with other ongoing projects in EU and U.S., I think the differences and challenges of LY03004 lies in several perspectives.

First, LY03004 is a complex LAI based on our microsphere technology platform. The U.S. FDA required a lot of information about the specification of drug release, as well as safety and efficacy in human trials for NDA review. Therefore, we have carried out detailed data analysis in the process of preparing the materials. The PK team from both sides have done a lot of work for days and nights.

Second, LY03004 is a long-term project. The pivotal clinical study was completed in 2015. No one in the international clinical team has participated the clinical studies of this project in the U.S. The data format on hand also failed to meet their requirements. We had no past experience to refer to since this is the first project in Luye that submitted NDA. Our team members have different backgrounds and experiences, so it is also a great challenge for us to get aligned in a short time. Therefore, the international clinical team and especially the statistical team immediately developed a submission strategy. We conducted multiple rounds of analysis and discussion of data requirements for the submission, assessing possible deficiencies, exploring issues that may be of concern to regulatory agencies during the review process, and continuously refining the data analysis. After three months, we completed all the tasks, and the completeness, accuracy and compliance of the data were ensured, laying a solid foundation for the successful submission of the submission.

China and U.S. teams celebrate the successful submission of FDA NDA

And also, the approval of Rykindo is based on global clinical data. Therefore, FDA also required us to provide clinical data from China and EU, as well as post-launch safety data in China. This is another difficulty for our submission, we have to translate and proofread all the Chinese data and re-analyze part of Chinese and EU data, in order to answer their questions. The clinical team faced the challenges and worked together to complete the data analysis and submitted a satisfactory response to FDA in a limited time frame.

Part of submission documents in the U.S. office

Q: As the PM of this project, I believe you must have a lot of unforgettable memories during the whole process, some are sweet, some are bitter. Can you share with us stories that impressed you the most?

Shi: It actually reminded me an old saying “The first step is always the hardest”. As the first project to submit application in the U.S., we met lots of difficulties. We finished clinical studies in August, 2015, and as long as we fulfill the manufacturing requirements then we can file NDA. However, the biggest problem was there is no commercial workshop. After rounds of discussions, the company finally decided to build our own GMP production line. We didn’t have any experiences in this area at first. Dr. Li Youxin took the lead to manage and coordinate this task and we were able to smooth out the work gradually. 
 

The other thing happened after we received the first CRL from FDA. Although this was common to most of the applications, we still received some doubts from the outside. Again, it was Dr. Li led the team to face the pressure and replied FDA’s questions in a calm way. This was indeed a difficult time for the whole team, but we were managed to face challenges and move forward. Dr. Dong mentioned about the importance of persistence which I felt the same. Drug development is a long and daunting process. No matter how difficult it is, we never gave up. I can’t remember how many days and nights, the team worked together to discuss and find solutions. Persistence is how we get to the end.

 NDA documents review, colleagues based in Yantai was in a teleconference with U.S. colleagues till 12 at night

Q: Commercialization is the next stage of Rykindo, which will be another long and difficult journey, do you have confidence in the future of this product in the U.S. market? How are we going to prepare for the product?

P: I think commercialization is probably not as difficult as the development of products, but the commercialization still requires significant resources to make it happen, because it involves a lot of activities and we have to do all these in a very accelerated pace. Normally you need 24-36 months to prepare for the launch, but now we are trying to launch the product within 6 months. We will need a suitable model and derive good economic value from a certain type of partner that has the capability to launch the product. We will have a decision on the commercialization model very soon.

Talking about the market, LAI products have huge market in the U.S. with a total value of $4.8 billion, the second biggest market is Spain with a value of $350 million. So the U.S. is definitely the major market for this product globally, and the market is still growing with a growth rate of 9% per year. For Rykindo, even if it was to carve out a small market share in this huge market, it is still a significant win for Luye. Rykindo will be the product that we can build the infrastructure on, it will lead the way for other products in the future.

Q: The submission of LY03004 in the U.S. requires a lot of collaboration between China and the U.S. How do you think about the collaboration between the two sides? What is the most important to a successful teamwork?

Shi: During the filing process, the team members from China and U.S. worked very well. We share the common sense of mission and collaborate to advance the project. Occasionally, there were conflicts in the process due to differences and I had to play a coordinating role as the PM of this project. I have to research and understand the divergent issues and clarify my thinking, and then communicate with the leaders of the relevant departments and get their approval afterwards. When it comes to successful teamwork, it require several things: first, there is a common goal and a common vision; second, there is core leadership and good decisiveness, for example, when filing the NDA in 2019, Dr. Li  was the President of Global R&D, he unified his leadership and made decisions, and made decisive and effective decisions in the communication with FDA. The third is that each team does its own job and complements each other, so that the effect of 1+1>2 can be achieved.

 

The project team went to the States for Pre-IND meeting

Dong: I feel deeply about the importance of teamwork. Drug development is a long term process. Not only does it require the professional quality and ability of each team member, but it also requires cross-departmental cooperation to achieve goals. Luye's strategic overseas development has its special characteristics: the overseas clinical and registration teams are relatively independent with limited manpower, a lot of information needs to be obtained from China, so the close collaboration between the US and Chinese teams is reflected in every stage of the filing. The first is the collaboration between the international registration team and the domestic non-clinical and CMC team. Most of the members of the international registration team have extensive experience, and play an important role in guiding and gate-keeping during the preparation of the filing materials. The domestic team actively cooperate and provide the required materials in a timely manner to ensure that the relevant filing materials are completed as scheduled. The domestic clinical, PK, and PV teams provided strong support during the later stages of the supplemental filing process. During the collaboration between the US and Chinese teams, every member involved did their best to keep the spirit of realistic discussion and not to pass the buck, so that the whole filing process could move forward smoothly. The most important factors for successful and efficient teamwork are mutual trust, openness and transparency, unity of purpose, and accountability, all of which are perfectly reflected in the collaboration between the U.S. and Chinese teams in this project.

P: The Rykindo team is just starting, but I can tell you how we manage the Seroquel team, because the Rykindo team will be very similar to that. For Seroquel, we have a global commercial and functional team with colleagues from Latin America, APAC, and China. It took some time for the team to be highly efficient and now the team functions very well. I think the key to that is a lot of communication, more than you would expect.

I've noticed that when you're dealing with issues in a big cross functional global team, it takes a little longer to solve because there are always language and cultural issues. But over time the team learns how to operate together quite well and becomes very effective in moving the project forward, making decisions, driving processes, making things happen. In my experience, if you have the right people on the team, they tend to stick around and the wrong people tend to leave, and you can be very efficient and make things happen. Even though the Seroquel team is operating through Zoom over the past few years, we still operate very efficiently and effectively together. I believe the Rykindo team will do the same over time.

Q: Can you share with us about your expectation for Rykindo and future pipelines in oversea markets?

Shi: The U.S. has more clinical experience with LAI than China, and there is significant market potential for Rykindo in the U.S. FDA approval is a gold standard in the industry, which is a strong recognition of our company and will help in the subsequent overseas application of other projects. I remember at Rykindo's internal celebration, Dr. Sun Kaoxiang said, "Some people think this is a late approval, but the significance of this product for the company and the entire Chinese pharmaceutical industry is extraordinary, because it is the first complex injection successfully approved in the United States. Rykindo is like a pioneer, laying a good foundation for our future products to go globally. We believe that through our efforts, we will eventually achieve the mission proposed by Chairman Liu Dianbo to make advanced technologies for better quality of life, and to be a leading global pharmaceutical company.

Dong: Rykindo's approval is significant. For the treatment of schizophrenia, both domestic and foreign authoritative guidelines recommend LAI as an important strategy to improve patients' treatment compliance and prevent relapse. We believe Rykindo will bring benefits to more patients. On the other hand, given that the FDA has the most stringent standards in the industry, the approval of Rykindo in the United States lays a solid foundation for opening the market in various countries and regions around the world. We are confident about Rykindo's future in overseas markets.

P: For Rykindo, it will depend on how the market evolves over time and when the generics for some of the other major products in the market enter. It will be a quick, highly energetic launch and slow uptake for Rykindo. We expect it would take several years to hit our peak in the marketplace. The next product behind Rykindo is LY03010. We aim to launch this product in the same market when Rykindo hit its peak. Since Rykindo will have paved the way for LY03010, it will be more efficient for us to launch the product. We have the confidence to be more successful with the second product. As we mentioned before, commercialization and implementing the plan is always a challenge. It takes time and investment, we have to be patient and see how that goes. But over the long term, I think we will be very happy with the performance of Rykindo.