First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland. We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Cracow, Wrocław, Poznań, Gdańsk, Warsaw, and Łódź. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics. All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years. FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.


Introduction
Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A (GLA). 1 This enzyme deficiency leads to accumulation of globotriaosylceramide (GL-3) and its deacylated form, globotriaosylsphingosine (lyso-GL-3), in plasma and in different cells throughout the body. Accumulation of GL-3 and lyso-GL-3 causes major organ damage which leads to multiorgan complications involving the central and peripheral nervous systems, kidney, and heart that decrease the quality of life and shorten lifespan. 1 FD is largely underdiagnosed and diagnosis is most often established only after the symptoms of target organ damage has already occurred. Early diagnosis and introduction of disease-specific treatment is essential to stop the disease progression at early stage and prevent from irreversible tissue and organ damage.
The introduction of enzyme replacement therapy (ERT) in 2001 revolutionized the treatment landscape of FD. Clinical studies have proven the efficacy of ERT in the treatment of FD. Specifically, it has been shown that ERT inhibits the progression of target organ damage and stabilizes or even improves organ function. Therefore, international standards and guidelines recommend ERT as the optimal treatment of FD, although for some patients with amenable mutations, an alternative oral chaperone therapy is also available. 2,3 The available ERT treatment currently includes recombinant α-galactosidase A enzymes: agalsidase alfa (Replagal, marketed by Shire) and agalsidase beta (Fabrazyme, marketed by Sanofi Genzyme). In the EU, both agalsidase alfa and agalsidase beta have been approved and available for 20 years. Agalsidase alpha and beta are administered every two weeks by intravenous infusion at a dose of 0.2 mg/kg and 1.0 mg/kg, respectively. 4,5 Although two ERT preparations are currently available and approved for the treatment of FD, there are ongoing debates as to what dose of agalsidase preparation may offer better target organ protection. Two recent national guidelines suggested that higher doses of the recombinant enzyme may result in better clinical outcomes, at least in males with a classic phenotype. 6,7 Until 2018, reimbursed ERT for FD was available in all EU countries except Poland, where only a limited number of patients who participated in clinical trials or compassionate drug use programs received the treatment. 8 To help patients with FD obtain access to the therapy, emphasize the challenges they face, and gain public attention, the Association of Families with Fabry Disease, with the help of medical professionals and parliament members, initiated several public campaigns such as "Where is Fabry," 9 "Who is Fabry," 10 and "Fabry Diseasea burning problem". 11 After an initial rejection of the application in 2014, the Polish Ministry of Health eventually included ERT for FD to the list of reimbursable drugs in 2019.
Initially, one of the major challenges in the treatment of FD in Poland was a lack of guidelines for diagnosis and management of the disease. 12 In 2020, an interdisciplinary group of Polish clinicians prepared a comprehensive position statement providing practical recommendations for physicians who treat patients with FD. The position statement was approved by the Boards of the Polish Cardiac Society, Polish Society of Inborn Errors of Metabolism, Polish Society of Internal Medicine, Polish Society of Nephrology, and Polish Society of Neurology. 13 The introduction of the reimbursable ERT was a major step towards the improvement of the quality of life of Polish patients with FD. However, to date, the results of this treatment program in Poland have not been published. The choice of one of the two available recombinant drugs was the sole decision of the treating physician, but patients had to be centrally approved for the participation in the program by a group of rare disease experts.

Methods
In 2021, two years after the introduction of reimbursed ERT therapy for FD in Poland, we designed a short survey to gather data on the FD patients currently treated in rare disease centers. The survey was distributed via e-mail to the FD attending physicians at seven largest academic centers in Katowice, Kraków, Wrocław, Pozna n, Gda nsk, Warszawa, and Łódź. The centers were selected based on the number of patients with FD treated. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics (gender, age,

REVISED Amendments from Version 1
We have updated the first version of our manuscript to address the reviewers' comments, particularly to explain the differences between East and West Poland in term of diagnosed Fabry disease cases and to emphasize the need of family screening and early treatment introduction. We hope that the changes improved the quality of our manuscript.
Any further responses from the reviewers can be found at the end of the article date of the qualification to the ERT program, age at the time of qualification, and time from the appearance of the first disease symptoms to the clinical diagnosis).
Data were analyzed using descriptive statistics and Statistica 13.1 PL (StatSoft Polska) software.

Ethics
The following study was non-interventional, questionnaire-based research, therefore, according to local regulations, Ethics Committee approval and patient informed consent were not required. The authors received permission to collect the data from all the centers involved and the patients' personal data were anonymized.

Results
All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). The mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years, although there was a substantial delay from the first clinical symptoms reported by the patients to the diagnosis -21.1 (8.9) years. The centers with the largest number of patients with FD was Łódź, Cracow, and Wrocław. Detailed numbers of the patients diagnosed and receiving ERT reported by each center in Poland are provided in Table 1.

Discussion
FD is still underdiagnosed in Poland since the reported disease prevalence and number of patients currently receiving the therapy is lower than in other EU countries. For example, in Germany, the estimated treated FD prevalence was 0.85 per 100,000 insured patients from 2010 to 2017, 14 which when extrapolated to the Polish population, may suggest that there should be at least 300 patients with FD that may require specific treatment. Lack of ERT reimbursement until 2018 seems to be the main cause of lower number of patients diagnosed with FD compared to other European countries, but data on FD incidence before ERT reimbursement are not available. The situation is improving since the survey showed that almost half (48%) of the Polish patients with FD are already on reimbursed ERT therapy. However, our study reflected some disproportion between eastern and western Poland in terms of number of diagnosed FD cases. This might be due to national fund criteria for medical centers that can be contracted for ERT, with only highly specialized facilities being eligible, therefore, some patients need to move to another province to receive treatment. Also, eastern Poland is less populated than western part. On the other hand, our study concerned only seven biggest centers, selected based on the number of patients with FD treated. Therefore, in eastern Poland there may be patients with FD diagnosed and treated, however, the study inclusion criteria did not capture them. Our findings reflect the important role that the program has already played, but much remains to be done to implement an effective nationwide screening strategy to identify undiagnosed FD patients. The screening should particularly concern high-risk groups, i.e., young patients with cardiovascular accidents and family members of patients already diagnosed with FD. Also, a close cooperation with a network of rare disease centers should be established to ensure that patients in Poland benefit fully from ERT. This project contains the following extended data: Explain the main reasons or obstacles as to why there are still patients not receiving disease-specific treatment despite it being reimbursed.

2.
We addressed all the comments as follows:

Introduction
(Line 9-10): I suggest emphasizing the importance of early treatment. Namely, disease-specific therapy is efficient only when started before irreversible changes develop. Due to that fact, it is also important to diagnose FD patients at an early age. ○ Author response: Thank you for raising this issue. We emphasized the need for early treatment introduction at the end of the first paragraph: "Early diagnosis and introduction of disease-specific treatment is essential to stop the disease progression at early stage and prevent from unreversible tissue and organ damage.".

Results:
If possible, it would be of great interest to also include in the Results data on how many families were affected. Namely according to Laney DA et al. 1 , family screening is very effective in diagnosing new patients as there were five family members diagnosed for every proband. ○ Author response: Unfortunately, we have no data on family connections of the investigated patients-this issue certainly needs to be explored in further research. We emphasized the need for family screening at the end of the Discussion section as follows: "The screening should particularly concern high-risk groups, i.e., young patients with cardio-vascular accidents and family members of patients already diagnosed with FD.". We also suggested screening patients with cardiovascular accidents at an early age due to the fact that this is quite a common symptom of FD bringing patients to emergency department units. Table 1: I would suggest renaming the first group of patients ("N of treated patients with FD" to "N of diagnosed patients with FD)", as it is duplicated and misleading. Also, check the numbers of treated patients with ERT -under Wroclaw numbers and sum are not correct. Check also the final sum of treated in the table and also in text.

○
Author response: Thank you for pointing this out, we have corrected and double-checked the numbers throughout the table and the manuscript.

Discussion:
In order to diagnose young patients (i.e. children) and females, the most effective way is family screening. I would suggest adding that fact to the discussion part and explain if it was done or not in Poland. It could be elaborated in a part where you mentioned "effective nationwide screening strategy", which is probably too vague expression and should be explained.

○
Author response: We emphasized the need for family screening at the end of the Discussion section as follows: "The screening should particularly concern high-risk groups, i.e., young patients with cardio-vascular accidents and family members of patients already diagnosed with FD." We also suggested screening patients with cardiovascular accidents at an early age due to the fact that this is quite a common symptom of FD bringing patients to emergency department units. Explain the main reasons or obstacles as to why there are still patients not receiving disease-specific treatment despite it being reimbursed.

○
Author response: To our knowledge, the main reason for some patients not receiving disease-specific FD treatment is the reimbursement criteria, which in Poland are particularly strict. Patients qualify to ERT if they are 8 years or older, have FD confirmed in both genetic