Source of following article：Pharmacube Pro WeChat official account, the author of Pharmacube Pro
Bi-specific antibodies have become a rising star in the sector of antibody. As of now, the FDA in the U.S. has approved BLA of three bi-specific antibody drugs: Amgen’s CD19/CD3 bi-specific antibody (indication: acute lymphocytic leukemia); Chugai Pharmaceutical’s anti-factor IXa/factor bi-specific antibody (indication: hemophilia A); Johnson & Johnson’s EGFR/c-Met bi-specific antibody (indication：non-small cell lung cancer). In addition, in May this year, EGFR/c-Met bi-specific antibody amivantamab was approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations that have progressed after platinum-based chemotherapy and took the development of antibody sector to a new level, not only because this is the first time FDA approves an antibody therapy targeting different tumor antigens, but also represents bi-specific antibody drugs’ milestone achievement in solid tumors treatment.
Image credit: NextPharma data base
According to Pharmcube NextPharma database, currently there are over 450 active bi-specific antibody projects under development globally, among which approximately 200 are in clinical stage, pharmaceutical giants like Roche, Amgen, Johnson & Johnson and AstraZeneca are all progressing multiple projects. In China, around 200 bi-specific projects (including pre-clinical stage) are under development. Many companies’ bi-specific antibodies have entered phase II/III clinical stage. Companies like Akeso, Inc. have become the pioneer in the bi-specific antibody sector.
By its exclusive Tetrabody technology, Akeso has developed various globally first-in-class bi-specific antibody projects, including PD-1/CTLA-4 bi-specific antibody Cadonilimab (AK104), PD-1/VEGF bi-specific antibody (AK112), PD-1/CD73 bi-specific antibody (AK131) and PD-1/LAG3 bi-specific antibody (AK129), etc.
As Akeso concentrates its efforts on Cadonilimab, this bi-specific antibody has obtained approval from the Center for Drug Evaluation (CDE) of the NMPA to initiate phase III clinical trial for first-line treatment of advanced cervical cancer. This is one of the most advanced bi-specific antibody clinical trials by domestic companies in China. Previously, Cadonilimab has obtained fast-track designation and orphan drug designation from the FDA for treating advanced cervical cancer. It was also included in the list of breakthrough therapy designation by CDE for the same indication.
Last month, at the 2021 ASCO Annual Meeting, Akeso published initial results of phase II clinical trial of AK104 (PD-1/CTLA-4 bi-specific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma (uHCC). Of 18 patients evaluable for antitumor activity, ORR was 44.4% (8/18), DCR was 77.8% (14/18). 2 patients of stable disease (SD) who had close to 30% reduction in tumor size from baseline. Median PFS has not been reached. Treatment-related adverse events (TRAEs) occurred in 83.3% of patients. Grade 3 TRAEs occurred in 26.7% (8/30), and no Grade 4 TRAEs or TRAEs leading to death. These data have showed the promising antitumor activity and an acceptable safety profile of Cadonilimab in combination with Lenvatinib for first-line treatment of uHCC.
Source of following video：Pharmacube Pro
As a matter of fact, up to now, no PD-1 based bi-specific antibody in the world has been approved in the market yet. Under this background, can Akeso’s Cadonilimab embark on its commercial journey spearheading its competitors? Apart from PD-1/CTLA-4 bi-specific antibody Cadonilimab, what other bi-specific antibody candidates are to be expected from Akeso? As for Akeso, what are the challenges with regard to bi-specific drug development? Recently at the first BioChina conference, Pharmacube Pro had the opportunity to interview Mr. Michael Xi, CFO of Akeso, about these questions.
Mr. Xi told Pharmacube Pro, “Akeso plans to submit NDA in China for Cadonilimab for treatment of cervical cancer in the third quarter of 2021, the company believes that Cadonilimab is expected to become the first PD-1 based bi-specific antibody drug worldwide that obtains market approval.”
Mr. Michael Xi, CFO of Akeso, Inc., interviewed by Pharmacube at the BioChina conference
Pharmacube Pro: since listing on Hong Kong Stock Exchange in April 2020, what development has Akeso achieved in general?
Michael Xi: In over a year’s time since our IPO on stock market, the company has achieved various breakthroughs. Firstly, in terms of product pipelines, as of today, we have 13 projects at clinical development stage, 3 of which entered clinical stage after the company listing. Over 40 clinical trials have been initiated, among which PD-1/CTLA-4 bi-specific antibody Cadonilimab (AK104) plans to submit NDA in the third quarter this year.
Secondly, in terms of corporate operation, the team size of our core management team has increased to 11 from 7 before IPO, with senior executives for commercialization, CMC/MST and BD joined, substantially improved the integrity of corporate operations. In addition, the team size of our employee has increased around three times to over 1,000 compared with 350, which was how many employees we had in the period of IPO. This played a crucial role in driving multiple projects at the same time.
Thirdly, as for production capacity, before the company went public, our GMP capacity was 3,500 L, which has now increased to 23,500 L, among which the manufacturing base in Guangzhou has gone into trial operations in January this year. Of course, this is not our upper limit. The company is still further expanding production capacity, in-operation and in-plan production capacity adds up to 83,500 L, which is in the leading position among biotech companies.
Pharmacube Pro: what are Akeso’s most iconic bi-specific antibody projects?
Michael Xi: our fastest progressed bi-specific antibody project is the globally first-in-class PD-1/CTLA-4 bi-specific antibody Cadonilimab (AK104). In January 2021, the enrollment of patients in registrational phase II clinical trial of Cadonilimab for treating patients with recurrent or metastatic cervical cancer has been completed. In April, AK104 has obtained approval from CDE to initiate the phase III clinical trial of Cadonilimab for first-line of advanced cervical cancer. Furthermore, since the company's IPO, Cadonilimab has made progress in studies of multiple other indications, obtained positive data for not only small indications such as mesothelioma, microsatellite instability-high (MSI-H) solid tumors, but also large indications such as gastric cancer, liver cancer, and non-small cell lung cancer. Based on the current data and clinical progress we have achieved, we are very confident that Cadonilimab will be the first commercialized PD-1 based bi-specific antibody worldwide.
PD-1/VEGF bi-specific antibody AK112 is another project that we achieved major clinical breakthrough in the past one year. As the results from phase I clinical study in Australia show, of patients who were insensitive to treatment with PD-1 antibody, AK112 has showed promising efficacy, ORR of phase Ia clinical trial was 23.2%, which was even better than Cadonilimab data-wise. Although this is comparison of early phase data, achieving such promising data from these refractory patients brings us great confidence in further clinical development. Based on these data, we have initiated clinical trials for various indications. We expect with confidence that in the next 12 months, AK112 is expected to achieve great breakthrough in multiple indications and become another core pipeline like Cadonilimab.
Pharmacube Pro: what are the challenges for Akeso in the following bi-specific antibody projects’ development?
Michael Xi: generally speaking, I think there are five major challenges to overcome. 1. The challenge of getting approval: currently no PD-1/PD-L1 bi-specific antibody has been commercialized. For regulators, this is a type of drug with brand new mechanism. Challenges exist in both efficacy evaluation and approval path rationalization. 2. The challenge of commercialization: for any type of product, obtaining approval is merely the first step of commercialization, how to get sales performance is another key challenge. 3. The challenge of manufacturing: from the perspective of manufacturing, compared to monoclonal antibody, bi-specific antibody has higher technical requirements, how to optimize cell line and increase productivity, is the common conundrum faced by antibody companies. 4. The challenge of indication expanding: take Akeso for example, our most rapidly developed indication is cervical cancer, which is yet a small indication. In the future we need to continue exploring and achieve breakthrough in large indications, to gain bigger market share. 5. The challenge of internationalization: for our case, many clinical trials are running in China domestically. To win over the global market, we need to emphasize the layout in global multi-center clinical trials.
Pharmacube Pro: looking into the next five to ten years, what are your expectations of the development of bi-specific antibody sector?
Michael Xi: as a matter of fact, the development of bi-specific antibodies mainly consists of integration of relatively well-developed targets. Therefore, innovation breakthrough is the first thing worth expecting, including bi-specific antibody development based on new targets and novel clinical protocols design. The breakthrough in these two aspects are crucial to bi-specific antibody drug’s innovation from the source.
Another breakthrough worth expecting is whether bi-specific antibody can be combined with other type of drugs, e.g. ADC. This kind of combination therapy may bring more effective treatment for patients. In addition, whether PD-1/PD-L1 based bi-specific antibody can act as new adjuvant treatment as PD-1 monoclonal antibody and intervenes in early stage treatment, is also worth looking forward to.
The third point worth expecting is that whether bi-specific antibody can successfully become the next-generation cornerstone product of oncology treatment, even to replace the role of PD-1 monoclonal antibody. This is the ambition of many companies who are developing PD-1/PD-L1 based bi-specific antibodies. Currently we have indeed seen the promising efficacy of this type of bi-specific antibody in many indications.
The last breakthrough worth looking forward to, in my opinion, is the battle of bi-specific antibody versus standard therapy or other target therapy. This is not only good for better showing the value of bi-specific antibody drugs, but also very rewarding commercially for bi-specific antibody companies, therefore eventually drives the next round of pharmaceutical innovation.