Professor Wu Depei and Professor Fu Rong: Looking forward to the innovative treatment of rare disease PNH, grasping the innovative context, and basing on the Chinese experience

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and fatal hematologic disorder caused by a mutation in the PIG-A gene of hematopoietic stem cells that impairs the function of complement regulators, resulting in uncontrolled

It is understood that the PNH innovative drug Crovalimab made its debut in the 18th National Red Blood Cell Disease (Anemia) Academic Conference of the Chinese Medical Association held recently, bringing hope

In the field of blood rare diseases, PNH patients have a risk of death within five years if left untreated, up to 35%.

C5 complement inhibitors are the standard regimen

In short, there are still many problems to be overcome in the field of PNH treatment in China, and the clinical demand for innovative drugs is particularly urgent

Crovalimab, as a new generation of C5 complement inhibitors, debuted at the National Conference on Red Blood Cell Disease (Anemia), can you please talk about the clinical progress of Crovalimab in combination with relevant research and share the efforts of Chinese clinical researchers in this regard?

The COMPOSER study, a Phase I/II open-label adaptive clinical trial of Crovalimab in the treatment of patients with ^PNH1, showed that:

• Crovalimab is able to block complement activity and control intravascular hemolysis (LDH response).
  
  
  In all patients without eclozumab therapy, the activity of the end-complement is completely blocked by Crovalimab, and patients without eclozumab treatment show immediate and sustained LDH reduction; In patients who switched from eculizumab to Crovalimab, end-complement activity was completely blocked by Crovalimab, and LDH levels in 6 patients fell to < 1.
  5 × ULN<b12> after treatment with Crovalimab.
  

Figure 1 Changes in complement activity and LDH levels in people who have not been treated with eclozumab

Fig.
2 Changes in complement activity and LDH levels in people converted from eclozumab to Crovalimab

• The overall need for blood transfusion decreases
  during treatment.
  
  80% transfusion avoidance rate in people who have not been treated with ecuizumab from baseline to week 20; The transfusion avoidance rate in people who switched from eclozumab to Crovalimab was 74%.
  
  

• Crovalimab is effective in patients with C5 polymorphisms who do not respond to ecuzumab
  .
  
  

Figure 3 Changes in complement activity after Crovalimab treatment in patients with C5 polymorphism

• Long-term follow-up studies have found that Crovalimab can continuously and stably control intravascular hemolysis, and most patients have stable hemoglobin and do not rely on blood
  transfusions.
  
  

• Crovalimab is safe and well
  tolerated.
  
  There were no treatment-related serious adverse events (SAEs) or AEs leading to the termination of the study, the most common AEs were nasopharyngitis, upper respiratory tract infections, and headaches, and breakthrough hemolytic (BTH) events were uncommon, at only 0.
  13 events/year
  of treatment.
  

Based on the good results achieved in the previous period, a Phase III clinical study on Crovalimab (COMMODORE 1/2/3)
was subsequently conducted.

The COMMODORE 1/2 study is an ongoing global Phase III clinical trial
of patients treated with PNH or first-to-treat patients receiving Crovalimab.

The COMMODORE 3 study was a phase III, multicenter, one-arm study of Crovalimab in the treatment of Chinese undergoing adult/adolescent (≥ 12 years old) PNH patients
.

The study enrolled 50 Chinese patients with common primary endpoints of the proportion of patients who avoided blood transfusions from baseline to week 25 and the proportion of patients who achieved hemolysis control from weeks 5 to 25, and the evaluation index was LDH≤1.
5ULN
.

Through the joint efforts of Chinese researchers, preliminary results show that the study has reached the common primary endpoint of reducing the proportion of LDH levels and avoiding the proportion of patients who avoid TA; The results have been submitted to the Drug Evaluation Center (CDE)
of the State Food and Drug Administration of China.

Recently, CDE has officially accepted the listing application for Crovalimab treatment PNH and granted priority accreditation
.

In the coming era of complement inhibitors, can you please look forward to the changes that may occur in the field of PNH treatment? What social implications could this have?

In the field of PNH treatment, the successive listing of complement inhibitors will further enrich the treatment options of PNH, improve the accessibility of medication, greatly improve the quality of life of PNH patients, and help patients achieve normal life and work
like other patients with chronic diseases.

At the same time, the clinic should pay more attention to the standardized application of new drugs and improve the treatment system
.

Chinese researchers have made great efforts in promoting the clinical trial of Crovalimab, which fully highlights the value of Chinese data to guide PNH treatment, and also looks forward to more "Chinese data" in the future, leading the development of
global PNH innovative treatment.

The social implications of the launch of innovative drugs will also be profound
.

Looking at the field of blood rare diseases, among the 121 rare diseases in China's "First Rare Disease Catalogue", there are as many as 14 kinds of
blood rare diseases.

The listing of innovative drugs related to blood rare diseases is expected to further meet the clinical needs of rare diseases, and help China to formulate or adjust relevant medical and health policies to effectively benefit rare disease patients
.

At the same time, this measure is expected to further promote the improvement of China's rare disease diagnosis and treatment system and promote the "ecology" of
rare disease treatment and protection.

In order to respond to the national call and effectively promote the development of the field of blood rare diseases, the Hematology Branch of the Chinese Medical Association is discussing the establishment of a working group related to blood rare diseases, and in the future, it is expected to rely on the platform to more systematically promote the development of various blood rare diseases, including PNH, carry out in-depth academic exchanges, and strive to build an efficient prevention and control system for blood rare diseases in China, comprehensively improve the level of clinical diagnosis and treatment, and help realize the national "Healthy China 2030" strategy
as soon as possible.

Professor Wu Depei

• Chief physician, professor, doctoral supervisor

• Director of the Department of Hematology, First Affiliated Hospital of Soochow University

• Executive Deputy Director of the National Clinical Medical Research Center for Hematological Diseases

• Deputy Director of Jiangsu Institute of Hematology

• Director of the Institute of Hematopoietic Stem Cell Transplantation of Soochow University

• Member of the 13th National Committee of the Chinese People's Political Consultative Conference

• Chairman of the Hematology Branch of the Chinese Medical Association

• Vice President of the Hematology Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Expert Committee of China Hematopoietic Stem Cell Donor Database

• Editor-in-Chief of Chinese Journal of Hematology

Professor Fu Rong

• Doctor of Medicine, Chief Physician, Second-level Professor, Doctoral Supervisor

• Vice President of Tianjin Medical University General Hospital, Director of Hematology Center

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Association

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Doctor Association

• Deputy Leader of the Red Blood Cell Group of the Hematology Branch of the Chinese Medical Association

• Chairman of the Red Blood Cell Disease Committee of the Beijing Society for Cancer Prevention and Control

• Deputy Leader of the China MDS/MPN Working Group of the Hematology-Oncology Professional Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Clinical Oncology Professional Committee of the Chinese Association of Women Physicians

• Member of the Standing Committee of the Hematology Expert Committee of the Cross-Strait Health Exchange Association

• Vice Chairman of the Hematology Branch of the Chinese Medical Association

• Chairman of Hematology Branch of Tianjin Medical Association

• Vice President of Hematology Branch of Tianjin Medical Doctor Association

• Co-editor-in-chief of the Journal of Clinical Laboratory Analysis

• Associate Editor, Chinese Journal of Hematology

• Jinmen medical talents, the first Tianjin famous doctors, Tianjin teaching famous teachers

• Author of "Chinese Expert Consensus on Aplastic Anemia", "PNH China Expert Consensus", "Pure Red Blood Cell Aplastic Disorder Chinese Expert Consensus"

References:

1.
Röth, Alexander et al.
“The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria.
” Blood vol.
135,12 (2020): 912-920.
 

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