On May 10, 2023, NMPA announced the resumption of the import, sale, and use of Albumin Bound Paclitaxel for Injection (Abraxane) produced by Celgene Corporation, the subsidiary of Bristol Myers Squibb (BMS). 

This marks the first "lifting" of the ban on this original drug from Bristol Myers Squibb (BMS) since its import was suspended in 2020. However, over the past four years, several generics have already entered the market and the market landscape of Albumin Bound Paclitaxel has already changed drastically. How will Bristol Myers Squibb (BMS) breakthrough? 

The brief history of the development of paclitaxel drugs 

Paclitaxel, a natural product extracted from taxus chinensis, acts on the microtubule to inhibit the mitosis of tumor cells and is one of the most important broad-spectrum chemotherapy drugs. Since its discovery in the 1960s, paclitaxel has been available on the market in the form of injections. 

In 1992, FDA approved the first paclitaxel injection (brand name: Taxol) for the treatment of advanced ovarian cancer. It was later approved for the treatment of other cancers, such as the breast cancer, NSCLC, and Kaposi's sarcoma. 

However, due to its poor water solubility, paclitaxel needs a complex solvent of polyoxyethylated castor oil and anhydrous ethanol to enhance its solubility. This type of solvent easily stimulates the release of histamine in the body, leading to severe allergies. Therefore, patients often require pre-treatment with adreno cortico hormones and antihistamines before administration to alleviate allergies. The administration regimen is complex. 

As a result, the next-generation paclitaxel drugs called Albumin Bound Paclitaxel (Abraxane) was developed. Abraxane uses human albumin as a carrier, allowing direct administration without the need for pre-treatment with adreno cortico hormones and antihistamines. 

Developed by Abraxis, a company in the United States, Abraxane was approved by FDA in January 2005 for the treatment of breast cancer under the brand name Abraxane, and later approved for the treatment of lung cancer, pancreatic cancer, etc. 

In 2010, Celgene made an acquisition of Abraxis for an upfront payment of USD 2.9 billion, gaining control of Abraxane. Since its marketing, the sales volume of Abraxane have been consistently increasing. 

In 2013, Abraxane was approved for marketing in China. In 2017, BeiGene obtained the sales right for the drug in Chinese market. According to the data from MENET, in 2018, the sales volume of Abraxane in public hospitals reached RMB 721 million, far surpassing other similar products. 

Albumin Bound Paclitaxel ban 

With the expiration of the patent of Abraxane, numerous generics have successively entered the market. In February 2018, the Albumin Bound Paclitaxel (Keaili) produced by CSPC Pharmaceutical Group Co., Ltd was approved for marketing; in August 2018, Aiyue , developed by Hengrui Pharmaceuticals, was approved for marketing; in November 2019, Qilu Pharmaceutical's Qilu Ruibei was also approved for marketing. 

In 2020, during the second round of national volume-based purchasing, Celgene was awarded the bid at a price of RMB 1,150/100ml, supplying provinces including Beijing, Tianjin, Zhejiang, and Hubei. The other two bid winners were CSPC Pharmaceutical Group (RMB 747/100ml) and Hengrui Pharmaceuticals (RMB 780/100ml). 

However, not long after Abraxane was selected, when NMPA inspected a commissioned production site of Bristol Myers Squibb (BMS) located in Illinois, the United States, it found that some key production facilities used in the production of Albumin Bound Paclitaxel did not meet the basic requirements of China's drug production quality management and there were issues with inadequate aseptic control measures in the production process, which did not comply with China's Good Manufacturing Practices for Pharmaceutical Products (2010 Revision). Therefore, the import, sale, and use of Abraxane in China were lawfully suspended. Subsequently, Bristol Myers Squibb (BMS) initiated a recall of Abraxane from the Chinese market. 

Regarding substitute supply, on March 27, 2020, the National Centralized Procurement Office issued the Notice on the Determination of Substitute Supply Companies for Paclitaxel for Injection (Albumin Bound) in Some Regions , confirming CSPC Pharmaceutical Group and Hengrui Pharmaceuticals as substitute supply companies for the original Celgene supply regions. This means that CSPC Pharmaceutical Group and Hengrui Pharmaceuticals will divide 70% of the committed purchase volume in 30 provinces and regions across China. 

In August of last year, BeiGene announced a settlement with Celgene and terminated the commercial cooperation for 3 mature products. As a result, all rights to Abraxane in China have been returned to Bristol Myers Squibb (BMS). 

The market landscape of paclitaxel undergoes changes, using combination therapies for breakthrough 

As of now, 7 domestic companies have obtained production approval document of Paclitaxel for Injection (Albumin Bound), including CSPC Pharmaceutical Group Co., Ltd, Hengrui Pharmaceuticals, Qilu Pharmaceutical, Kelun Pharmaceutical, Hisun, Kanghe Biopharmaceutical and Haichang Biotech. 

In response to competition from generics, these companies are exploring combination therapies involving Albumin Bound Paclitaxel and PD-1. In December 2021, Hengrui Pharmaceuticals's PD-1 monoclonal antibody, camrelizumab, in combination with Albumin Bound Paclitaxel, obtained NMPA approval for the first-line treatment of two new indications: advanced squamous NSCLC and esophageal squamous cell carcinoma. Innovent's sintilimab in combination with Albumin Bound Paclitaxel is undergoing research for the treatment of recurrent cervical cancer, while Henlius's serplulimab has been approved for the combination with Albumin Bound Paclitaxel for the first-line treatment of the indication, locally advanced or metastatic squamous NSCLC .

The competition in the domestic Albumin Bound Paclitaxel market has intensified. Reform from multiple aspects is required for Abraxane to regain its former market position. 

Ref.

1.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.1056/NEJMoa1304369. Epub 2013 Oct 16. PMID: 24131140; PMCID: PMC4631139.

2.https://clinicaltrials.gov/study/NCT02017015?locStr=China&country=China&distance=50&term=Abraxane&aggFilters=phase:2,status:com&cond=Pancreatic%20Cancer&rank=1.

About  the Author:    

Yefenghong

Ye  Fenghong, a medical editor specializing in oncology at a healthcare internet  company, has conducted in-depth research on the pathogenesis and clinical  treatment of lung cancer and breast cancer. She has previously been involved  in the design and synthesis of anti-tumor drugs and has some experience in  computer-aided drug design. She is currently devoted to introducing  cutting-edge cancer treatment drugs to a wide range of readers, aiming to  help more people avoid cancer pain and embrace good health.