Professor Fu Rong: Innovative drugs drive the development of rare disease diagnosis and treatment, and the dilemma of PNH treatment in China is expected to be broken

In order to help promote the construction of "Healthy China" and promote the development of rare disease diagnosis and treatment in China, the 2022 China Rare Disease Conference was successfully held
in Beijing in the form of offline and online.
With the theme of "Life First, Shared Health", many workers in related fields deeply discussed the frontier hot
spots in the field of rare diseases in the new era.
Paroxysmal nocturnal hemoglobinuria (PNH), as a member of the rare disease family, has long been limited in its treatment in China, and patients have an urgent
need for innovative drugs.
Based on this, Yimaitong specially invited Professor Fu Rong of the General Hospital of Tianjin Medical University to share cutting-edge progress based on the current situation of PNH, and look forward to the prospects
of PNH treatment.

As a rare disease, PNH has gradually attracted clinical attention due to its typical clinical manifestations and many limitations in diagnosis and treatment, can you briefly introduce the current situation in the field of PNH in China?

PNH is a rare disease in which the function of complement regulators is impaired due to mutations in the PIG-A gene in hematopoietic stem cells, resulting in uncontrolled complement activation, and the clinical manifestations are three typical symptoms, such as intravascular hemolysis, potential hematopoietic failure, and thrombotic tendency1
.
The global incidence of PNH is about 1.
3 per million ^population2, and there is currently no national PNH epidemiological survey data in China, and previous local data show that the incidence of PNH is 1.
3-2.
85 per million ^population3
.
Registering and counting PNH cases nationwide is crucial
to grasping the trend of PNH epidemic in China and formulating relevant policies.

Although PNH is a benign clonal disease, the overall survival rate of PNH patients in China is still poor, and the 10-year overall survival (OS) rate is similar
to that of foreign countries many years ago.
In addition, PNH is often accompanied by many complications, such as fatigue (96%)6, anemia (89%)⁷, renal insufficiency (64%)⁸, dyspnea (66%)6, erectile dysfunction (47%)^{6, etc.
6}, resulting in a poor
overall quality of life.

In general, the current situation in the field of PNH in China is not optimistic, and it is necessary to pay attention to PNH patients from multiple levels and find ways
to improve the current situation.

Yimaitong: Internationally, C5 complement inhibitors have been widely used
as classical therapies for PNH.
Based on the actual situation in China, can you talk about the unmet clinical needs of PNH patients in China?

In the context of "no drug available", the current treatment methods of PNH in China are very limited, and the "Chinese Expert Consensus on the Diagnosis and Treatment of Paroxysmal Nocturnal Hemoglobinuria" formulated by the Red Blood Cell Disease Group of the Chinese Medical ^Association4 The recommended conventional traditional treatment methods for PNH include glucocorticoid therapy, symptomatic supportive therapy, immunosuppressant therapy, antithrombotic therapy, etc.
, which not only have poor hemolysis control, but also long-term frequent treatment may bring many problems
to patients, such as infection, pulmonary hypertension, and renal function damage.
For critically ill patients, hematopoietic stem cell transplantation is currently the only curable method, but factors such as difficult matching and graft-versus-host disease (GVHD) seriously limit its clinical application
.
PNH patients have a very urgent need for innovative drugs, and their survival and quality of life need to be improved
.

In addition to traditional C5 complement inhibitors, the academic community has been exploring a variety of new target drugs for PNH
.
Could you please briefly describe what makes the innovative mechanism of complement drugs unique? What is the efficacy and safety?

C5 complement inhibitors can effectively alleviate intravascular hemolysis in terms of mechanism, but because of C3-mediated continuous extravascular hemolysis, some patients treated with this drug cannot improve their anemia and cannot be separated from blood transfusion, and C5 complement inhibitors currently require intravenous infusion, and the patient's medication experience needs to be improved
.
The oral factor B inhibitors in clinical trials in our center can control both intravascular hemolysis and extravascular hemolysis
by inhibiting the proximal pathway of the complement system.

Figure 1 Mechanism of action of factor B inhibitors

Clinical trial data are available, and an interim analysis of a multicenter, randomized, open-label phase II study showed benefits in reducing serum lactate dehydrogenase (LDH) levels, improving Hb levels, and reducing transfusion dependence^, and was generally well tolerated5
.
The ongoing APPLY-PNH Phase III clinical trial has also shown superiority of factor B inhibitors over controls
.

Combined with relevant progress, it can be seen that factor B inhibitors, as a new mechanism of PNH therapy, have shown good potential in controlling hemolysis.
At the same time, oral administration can also improve patient compliance and improve patients' medication experience
.

Yimaitong: The emergence of innovative drugs may have a profound impact on the PNH treatment landscape, can you please look forward to the future changes in the treatment goals of the PNH field? What are the directions of efforts of domestic workers in related fields?