A Brief Discussion on Roxadustat in the Midst of the Controversy

Recently, there is a good news for roxadustat, which is in the midst of the controversy. On August 19, 2021 local time, Astellas Pharma Inc. and FibroGen jointly announced that roxadustat was approved by the European Commission (EC) for adult patients with symptomatic anemia of chronic kidney disease (CKD) (see Image 1 for information on official website of FibroGen).

Image 1 From official website of FibroGen

Part I: Basic knowledge of the product 

As the world's first small molecule hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) to treat renal anemia, roxadustat could promote the generation of erythrocytes by increasing the production of endogenous erythropoietin, improving iron absorption and mobilization, and down-regulating hepcidin. In 2019, scientists who discovered the mechanism of hypoxia-inducible factors were awarded the Nobel Prize in Physiology or Medicine, and the birth of roxadustat based on the relevant scientific research achievements has attracted much attention. Roxadustat was independently developed by American FibroGen, while AstraZeneca is responsible for its registration and commercial promotion in China, the United States, other American markets, Australia/New Zealand and Southeast Asia. The development and commercialization in Japan, Europe, Turkey, Russia, Commonwealth of Independent States, Middle East and South Africa lies on Astellas Pharma Inc. 

Part II: Registration process of roxadustat in China 

AstraZeneca is responsible for the registration and commercial mutual promotion in China in accordance with the agreement between FibroGen and AstraZeneca; while FibroGen (China) Medical Technology Development Co., Ltd. is the producing medical supplies manufacturer. 

In 2010, roxadustat was approved to conduct clinical research in China. In October of the same year, Phase I clinical trial was launched. From July 2011 to 2013, the Phase II multi-center clinical research of roxadustat was carried out and completed in 13 centers across the country. In August 2015, roxadustat was approved for Phase III clinical trial. In 2016, the Phase III clinical trial of roxadustat for dialysis and non-dialysis CKD anemia was officially launched in China, and it was completed in 2017. In August 2017, an application for market in China was submitted by roxadustat. 

On December 17, 2018, roxadustat passed the priority review process in China, and was approved for the treatment of renal anemia in dialysis patients, becoming the first orally small molecule HIF-PHI new drug for the treatment of renal anemia. Roxadustat has also become an innovative drug that was launched in China for global orientation, which drew global attention. On August 16, 2019, roxadustat passed the priority review process and was approved for the treatment of renal anemia in non-dialysis patients. 

According to the review report of roxadustat published by CDE, 41 clinical trials have been completed worldwide and more than 10,000 subjects have been enrolled in the roxadustat clinical project. The clinical trials enrolled 2,333 subjects who had been treated with roxadustat, 213 of whom had taken roxadustat for more than 1 year. It can be said that sufficient long-term data are available. In addition, the critical Phase III clinical research 808 confirmed the efficacy of roxadustat in the treatment of anemia in patients with non-dialysis chronic kidney disease. 

The post-authorization requirements in the review report also show that the following studies shall be completed: 1) Post-Authorization Safety Study (PASS), 2) Detection Identification & Monitoring (DIM), and 3) Dose Optimization Study. Currently, the applicant has submitted a clinical trial protocol for a post-authorization study through a supplementary application. 

As for the compliance of R&D, the Technical Review Report of Roxadustat Capsules (CXHS1700019-20) Application for Marketing shows that: 

Verification of development site: Beijing Municipal Bureau conducted verification of development site on FibroGen (China) Medical Technology Development Co., Ltd. and Shanghai WuXi AppTec. The addresses were respectively Unit 2, No.7 Medium-sized Enterprise Building, No.88 Courtyard, Sixth Kechuang Street, Beijing Economic-Technological Development Area, Beijing, and Building 45, No.299, Fute Middle Road, Waigaoqiao Free Trade Zone, Shanghai. The result is passed. 

Sample testing: According to the quality standard approved by the Center, Chinese Academy of Inspection and Quarantine tested the products (specification of 20mg and 50mg), and all of them meet the requirements. 

GMP compliance: The applicant provided the GMP compliance statement of the API and capsule manufacturer, the notice of the name change of applicant, the technology transfer statement, the patent authorization and the patent non-infringement statement, the commission agreement, the notarized certification documents of the overseas research institutions, etc. 

Verification of production site: From September 7 to 13, 2018, the Audit and Inspection Center of the National Bureau carried out on-site inspection on the drug registration and production of roxadustat capsules submitted by FibroGen (China) Medical Technology Development Co., Ltd. Opinions of the Audit and Inspection Center: 1. The on-site inspection of the production process is consistent with the approved/declared process, and no problem of authenticity is found. 2. In 2015 and 2017, the production process of 20mg and 50mg products was separately loaded in accordance with the theoretical batch of 20kg of total mixed particles into two specifications. In 2018, it was recommended by Center for Drug Evaluation that each batch of total mixed particles be used to produce single-size preparations, and it was not recommended to pack capsules of different specifications. In May 2018, the company promised in pharmacy supplementary information that in commercial production, each batch of total mixed particles is only used to produce a single size of preparation, but by the inspection, the company has yet completed 3 batch of process validation of its promise (in the dynamic inspection, each batch of total mixed particles is only used to produce a single size of preparation, and the theoretical batch is 20mg: 200,000 particles, and 50mg: 80,000 particles). 

In view of the above process verification problems, it is considered through technical joint review and discussion that after the on-site inspection, the company reverified the process of the two specifications of preparations as required: batch number of API used for process validation batch 20mg specification (confidential); and batch number of API for 50mg specification (confidential). Among them (confidential), the intermediate FG-6347 used in the two batches is two-step crystallization, which is consistent with the approved/declared process. The intermediate FG-6347 used in the other four batches of API is one-step crystallization, which is inconsistent with the approved/declared process. In view of the fact that only two batches of preparations corresponding to the intermediate FG-6347 used in API are two-step crystallization in the company's reprocess validation, it is suggested that the Center for Drug Evaluation shall pay more attention to it during the three-in-one review. The result of on-site inspection is "passed". 

Later, on November 23, 2018, CDE held a pharmaceutical professional meeting. They believed that, based on the existing data, the risk of this product was controllable and acceptable from the perspective of technical analysis. 

The Verification Center had organized an verification team from June 22 to 28, 2018, and carried out on-site verification on the clinical trial data of the drug according to the Key Points of On-site Verification of Drug Clinical Trial Data (CFDA No. 228 Announcement in 2015). From July 9 to 10, 2018, the Verification Center held a review meeting of drug clinical trial data, listened to the inspection team's report on the on-site verification, and reviewed the problems found and the explanations of problems submitted by the registered applicant and the inspected units. On July 12, 2018, the Verification Center held a communication meeting, and discussed about the on-site verification and joint review with the registered applicant. The applicant unit had no objection to the conclusion of the expert meeting. 

The inspected units include Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, the First Affiliated Hospital with Nanjing Medical University, Zhongda Hospital Southeast University, and Covance Pharmaceutical R&D (Shanghai) Co., Ltd. After the verification, it was found that there were mainly normative problems instead of authenticity in the clinical trial, including subjects screening/enrolling; traceability of clinical trial data; violation of the project; records and reports on the safety; management and record of experimental drugs; problems in transportation, handover and preservation of biological samples. After the verification, it was found that there were multiple cases of AE not reported in all 4 research centers due to the negligence of researchers or the fact that the researchers combined the subjects' past medical history, primary disease characteristics, clinical symptoms, signs and other conditions to determine the abnormal values in laboratory tests as NCS and did not report AE. There were no new unexpected or clinically uncontrollable safety issues in the unreported AE. The existing nonconforming items have no significant impact on the efficacy and safety evaluation of the product and do not change the interpretation of this product's clinical benefit/risk. 

Part III: FDA declined to approve. 

FibroGen's official website released FibroGen Receives Complete Response Letter from the FDA for Roxadustat for Anemia of Chronic Kidney Disease on August 11, 2021. It is mentioned therein that "The letter indicates the FDA will not approve the roxadustat NDA in its present form and has requested additional clinical study of roxadustat be conducted, prior to resubmission." It means that FibroGen needs to add new clinical trial data as required by the FDA if it wants to reapply. (Refer to the screenshots below) 

FDA Briefing Document-Roxadustat and Roxadustat for the Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients not on Dialysis and on Dialysis released on FDA official website on July 15, 2021 both questioned the safety of Roxastat: 

From the screenshots of the above documents, roxadustat is more risky in dialysis-dependent (DD) patients than epoetin-alfa in terms of cardiovascular safety. When it is compared with placebo, the risk was even higher in non-dialysis dependent (NDD) patients. 

Corresponding to the information in the FDA documents, the CEO of FibroGen said on April 6, 2021: "As members of senior management were preparing for an upcoming FDA Advisory Committee Meeting, we realized that the primary cardiovascular safety analysis includes temporary adjustments to the stratification factors. Although all of the following analyses, including differences in stratification factors, were included in the NDA application materials, the company immediately decided to clarify this issue with the FDA and communicate with the scientific and investment communities." At the same time, FibroGen has initiated a comprehensive internal review to ensure that such issues will not occur in the future. 

Part IV: Registration progress in other areas

 Based on the information available at present, except for the approval in Chinese market, roxadustat has also been approved in Japan, Chile, and Korea for the treatment of CKD anemia in dialysis-dependent (DD) and non-dialysis dependent (NDD) adult patients. 

On September 20, 2019, roxadustat was approved in Japan under the trade name of Evrenzo to treat anemia in dialysis patients with chronic kidney disease; In December 2020, Japanese Ministry of Health, Labour and Welfare (MHLW) approved Evrenzo (Chinese trade name: Ai Ruizhuo, common name: roxadustat) to be used for non-dialysis dependence (NDD) 

Part V: High attention has been paid to EC's approval of roxadustat in the industry. 

August 19, 2021 local time is definitely unusual for FibroGen, because EC approved roxadustat, and FibroGen announced the news on its official website to boost market confidence. 

In the EU market, Astellas Pharma Inc. is responsible for the registration and promotion of roxadustat, whose trade name is Evrenzo. 

In Summary of Opinion-Initial Authorization released on June 24, 2021, EMA expressed its positive points of view: On 24 June 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Evrenzo, intended for the treatment of anaemia symptoms in patients with chronic kidney disease. The good news may make the management of FibroGen and Astellas Pharma Inc. in a good mood. 

Conclusions 

With EC's approval of roxadustat in the EU market, FibroGen and its business partners were temporarily relieved and strengthened their confidence. However, given the authority of the FDA in the international pharmaceutical market and the safety, data regulation and management issues raised by the FDA in the review documents, 

It is believed that roxadustat will be concerned and supervised by local drug administration officials in the future use. As the main parties of MAH, they should actively fulfill their legal responsibilities, carry out the safety research of post-authorization, and supplement the deficiencies in clinical research with real post-authorization evidence. As for the future of roxadustat in the United States market, it remains to be seen cautiously. 

References: 

1. Official website of FibroGen 

2. Technical Review Report on the CDE Application for Marketing of Roxadustat Capsules in China 

3. Review information on EMA official website 

4. Information on FDA official website 

About the Author:

zhulikou431

Zhulikou431, as a senior engineer, PDA member, ISPE member, ECA member, PQRI member, senior aseptic GMP expert, has deep knowledge in aseptic process development and verification, drug development and registration, CTD document writing and review, regulatory audit, international certification, international registration , quality system construction and maintenance, as well as sterile inspection, environmental monitoring and other fields. In recent years, he has focused on the analysis of trends in the macro pharmaceutical field and the risk management of pharmaceutical enterprise mergers and acquisitions projects.