On Roxastat in the vortex of controversy

Roxastat, who has been in a whirlpool of controversy recently, finally ushered in good news: On August 19, 2021 local time, Astellas and Faberge announced that Roxastat was approved by the European Commission (EC).
For the treatment of adult patients with symptomatic anemia associated with chronic kidney disease (CKD) (see Figure 1 for information on the official website of Fabojin)
.

Figure 1 from the official website of Fabojin

Part 1: Basic product knowledge

Part 1: Basic product knowledge

Roxastat is the world’s first small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) to treat renal anemia.
It can increase the production of endogenous erythropoietin and improve iron The absorption and mobilization and down-regulation of hepcidin promote red blood cell production
.

In 2019, scientists who discovered the mechanism of hypoxia-inducible factors were awarded the Nobel Prize in Physiology or Medicine.

Part 2: The registration process of Roxastat in China

Part 2: The registration process of Roxastat in China

According to Fa Bo into the company and AstraZeneca agreement, registration and commercial transactions carried out in China in the mutual promotion, responsible for AstraZeneca; and manufacturers are into the enamel Bo (China) Pharmaceutical Technology Development Co.
, Ltd
.

In 2010, Roxastat was approved to conduct clinical research in China
.

In October of the same year, the phase I clinical trial was launched; from July 2011 to 2013, the multi-center phase II clinical study of roxastat was completed in 13 centers across the country; in August 2015, the phase III clinical trial of roxastat was obtained Approval; In 2016, the China III clinical trial of roxastat for dialysis and non-dialysis CKD anemia was officially launched and completed in 2017; in August 2017, roxastat has submitted a listing application in China

On December 17, 2018, Roxastat was approved for the treatment of renal anemia in dialysis patients in China through the priority review process, becoming the first oral small molecule HIF-PHI new drug for the treatment of renal anemia
.

Roxastat has also become the first innovative drug to be marketed in the world for the first time in China, which has aroused global attention; on August 16, 2019, Roxastat was approved to treat non-dialysis patients with renal anemia through the priority review process

From the evaluation report of Roxastat published by CDE, we can see that the product has completed 41 clinical trials worldwide, and more than 10,000 subjects have been selected for rosastat clinical projects
.

In the completed clinical trials, a total of 2333 subjects received rosarestat treatment, and 213 of them were treated for more than one year, and sufficient data on long-term medication was obtained

In the post-marketing requirements of the review report, it is also proposed that the following studies should be completed: 1) Post-marketing safety study (PASS), 2) Key monitoring study (DIM), 3) Dose optimization study.
At present, the applicant has submitted a supplementary application for listing Post-research clinical trial protocol
.

Regarding R&D compliance, the "Roxastat Capsule (CXHS1700019-20) Application for Listing Technical Evaluation Report" mentioned:

◆Research and development site verification: The Beijing Municipal Bureau conducted research and development on-site verification of Fabojin (China) Medical Technology Development Co.
, Ltd.
and Shanghai WuXi AppTec New Drug Development Co.
, Ltd.
The locations of the verification were Beijing Economic and Technological Development Zone Kechuang VI.
Unit 2, No.
7 Medium Enterprise Building, No.
88 Street, Building 45, No.
299, Fute Middle Road, Waigaoqiao Free Trade Zone, Shanghai
.

The conclusion is passed

◆Sample inspection situation: The China Inspection Institute inspected the product (specification 20mg) and product (specification 50mg) in accordance with the quality standards approved by the center, and they all met the requirements
.

◆GMP compliance: the applicant provided the GMP compliance statement of the API and capsule manufacturing plant, the notification of the change of the name of the reporting unit, the technology transfer statement, the patent authorization and the patent non-infringement statement, the entrustment agreement, and the notarized overseas research institution Documented evidence and so on
.

◆Production site inspection: The National Bureau's Audit and Inspection Center conducted an on-site inspection of the drug registration and production of Roxastat capsules declared by Fabojin (China) Medical Technology Development Co.
, Ltd.
from September 7 to 13, 2018
.

The audit opinion of the audit inspection center: 1.

In response to the above process verification issues, the technical meeting discussed that: After the on-site inspection, the company re-verified the two specifications of the preparations as required
.

The batch number of the API used in the process verification batch of 20 mg (confidential); the batch number of the API used in the 50 mg batch (confidential)

Later, on November 23, 2018, CDE held a pharmacy professional meeting to discuss that, based on existing data, this product is technically controllable and acceptable
.

◆The Verification Center organized a verification team from June 22-28, 2018, according to the contents of the "Key Points for On-site Verification of Drug Clinical Trial Data" (CFDA Announcement No.
228, 2015).
On-site verification of the data was carried out
.

From July 9th to 10th, 2018, the verification center held a drug clinical trial data verification review meeting, listened to the verification team’s report on the on-site verification, and explained the problems found and the problems submitted by the registration application unit and the inspected unit The review

The verification unit including Ruijin Hospital, Shanghai Jiaotong University, Xinhua Hospital, Shanghai Jiaotong University, the First Affiliated Hospital of Nanjing Medical University, Zhongda Hospital, Southeast University, Covance Pharmaceutical R & D (Shanghai) Co.
, Ltd
.
After verification, no authenticity problems were found in the clinical trial, which were mainly regulatory issues: subject screening/enrollment; clinical trial data traceability; protocol violation; safety records and reports; experimental drug management and records; biological sample transportation , Handover and preservation issues
.
The verification found that there were multiple underreporting of AEs in the 4 research centers, partly due to the negligence of the investigator, and partly because the investigator combined the subjects’ previous medical history, characteristics of the primary disease, clinical symptoms, signs and other conditions on laboratory examinations If the value is judged to be NCS, but AE is not reported
.
There were no new unexpected or clinically uncontrollable safety issues in underreporting AEs
.
The existing unqualified items have no significant impact on the effectiveness and safety evaluation results of this product, and will not change the clinical interpretation of the benefits/risks of this product
.

Part 3: FDA refused to approve

Part 3: FDA refused to approve

On August 11, 2021, FibroGen's official website released "FibroGen Receives Complete Response Letter from the FDA for Roxadustat for Anemia of Chronic Kidney Disease"
.
It mentioned: 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.
This means that if FibroGen wants to reapply again, it needs to follow FDA requirements Supplement new clinical trial data
.
(See screenshot below)

On the official website of the U.
S.
FDA, it is found that the 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 July 15, 2021 are both against rosarestat.
The safety of the product is questioned:

According to the screenshot of the above file, it can be seen that in terms of cardiovascular safety, rosastat is at a higher risk in dialysis-dependent (DD) patients compared with epoetin-alfa; and in non-dialysis-dependent (NDD) patients Compared with placebo, the risk is higher
.

Corresponding to the information in the FDA document, on April 6, 2021, the CEO of FibroGen said: “As senior management members are preparing for the upcoming FDA Advisory Committee meeting, we realize that the main cardiovascular safety The analysis includes temporary adjustments to stratification factors
.
Although all the following analyses, including differences in stratification factors, are included in the NDA filing materials, the company quickly decided to clarify this issue with the FDA and communicate with the scientific and investment communities
.
At the same time, it said that FibroGen has begun a comprehensive internal review to ensure that such problems will not occur in the future
.

Part 4: Registration progress in other regions

Part 4: Registration progress in other regions

According to the information currently available, in addition to the approval of Roxastat in China, Roxastat has been approved in Japan, Chile, and South Korea for the treatment of CKD anemia in adult patients on dialysis (DD) and non-dialysis (NDD)
.

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

Part V: EC approved Roxastat, the industry continues to pay great attention

Part V: EC approved Roxastat, the industry continues to pay great attention

On August 19, 2021 local time, it is destined to be unusual for FibroGen
.
Because the EC approved rosastat, FibroGen's official website made a high-profile announcement to boost market confidence
.

In the EU market, Astellas is responsible for the registration and promotion of Roxastat products under the trade name Evrenzo
.

In the "Summary of opinion-initial authorisation" released on June 24, 2021, EMA expressed its positive opinion: 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 arrival of this good news should give the management of Fabojin and Astellas a good mood
.

Summarize

Summarize

Although the EC approved Roxastat to be listed on the EU market, Fabojin and its business partners were temporarily relieved and strengthened their confidence
.
However, in view of the authority of the US FDA in the international pharmaceutical market, as well as the safety issues and data regulatory issues raised by the FDA in the review documents, I believe that rosarestat will be used by local drug authorities in the future.
Pay attention to and strengthen supervision; and as the main body of MAH, it is necessary to actively perform legal responsibilities, actively carry out post-marketing safety research, and use solid post-marketing real-world evidence to supplement the deficiencies in clinical research
.
As for the fate of rosastat in the US market, we still need to be cautious and wait-and-see
.

Reference materials:

1-FibroGen official website

2-China CDE Roxastat Capsule Application Technical Evaluation Report

3-EMA official website review information

4-FDA official website information