Pompe disease is a rare progressive metabolic myopathy, resulting in a fatal outcome, in the world its frequency is about 1 case per 40,000. Other names of Pompe disease: a disease of accumulation of glycogen of type II (GSD- II), deficiency of acid maltase (AMD) and type II glycogenesis. Pompe disease refers to lysosomal accumulation diseases, as it occurs as a result of a deficiency of the natural lysosomal hydrolase, acidic α-glucosidase (CAG), which ensures the breakdown of glycogen to glucose. The lack of this enzyme causes accumulation of glycogen in various tissues, especially in the heart, respiratory and skeletal muscles, leading to the development of hypertrophic cardiomyopathy and progressive muscular weakness, including impairment of respiratory function. The clinical spectrum of manifestations of Pompe disease is characterized by its various forms - from rapidly advancing infant, or infantile (the appearance of symptoms during the first year of life, predicted life expectancy is very short), to a slowly progressive form with a late onset of the disease.
Infant form of Pompe disease is characterized by massive sedimentationglycogen in the heart and skeletal muscles, which always leads to the development of rapidly progressing cardiomyopathy, generalized muscle weakness and hypotension. The development of motor skills often stops completely, or if they reach a certain stage of their development, they are subsequently lost. Death occurs mainly because of cardiac and / or respiratory insufficiency until the age of 1 year.
In a retrospective study of the natural course of the disease in patients with infantile Pompe disease (n= 168), the mean age at onset of symptoms was 2.0 months, and the mean the death rate was 9.0 months. Kaplan-Meier survival rate at the age of 12, 24 and 36 months was, respectively, 26%, 9% and 7%.
An atypical, more slowly progressing variant of the infantile form of Pompe disease, characterized by less severe cardiomyopathy and therefore a longer life expectancy, was described.
Clinical manifestations of Pompe disease with late onset may first appear in the period of neonatal, childhood, adolescence or even in adulthood.This form of the disease progresses much more slowly than the infant form. It is usually characterized by the presence of a residual activity of CAG, sufficient to prevent the development of cardiomyopathy, but some changes in the heart have been described in approximately 4% of patients with late-onset Pompe disease.
Patients with late-onset Pompe disease usually have progressive myopathy, mainly the proximal muscles of the upper and lower extremity belt, as well as various degrees of impaired breathing function, eventually progressing to absolute disability and / or necessity to carry out artificial ventilation of the lungs. The period of progression of the disease is very variable and can not be predicted: in some patients, skeletal and respiratory muscle disorders occur early, which leads to loss of ability to move and respiratory failure; in others, progression is slower, and there is still a group of patients who report a mismatch in the progression of the disease when comparing changes in the skeletal and respiratory muscles.
Mechanism of action
It is assumed that Mayozaim restores the activity of lysosomal CAG, leading to the stabilization or restoration of the functions of the heart and skeletal muscles (including the respiratory muscles). Due to the presence of the blood-brain barrier and the size of the enzyme molecule, the capture of alglucosidase alpha at the level of the central nervous system is unlikely.
Clinical efficacy and safety
Infant form of Pompe disease; Clinical trial with patients aged 6 months and less
The safety and efficacy of Mayoim was evaluated in a basic retrospective randomized open-label study in 18 patients with an infantile form of the disease that does not require respiratory support, at the age of 6 months or less at the time of initiation of therapy. The retrospective group not receiving therapy was selected according to the baseline study group, its data were taken from a retrospective study with a study of the natural course of the diseasen= 42) patients with infant Pompe disease. Patients were randomized to receive 20 mg / kg or 40 mg / kg of the drug once every two weeks for 52 weeks.After 52 weeks, 16 of these 18 patients were included in the continuation phase of the clinical trial for subsequent treatment at the same dose, and the total duration of therapy was about three years (150 weeks).
The primary endpoint was the proportion of live patients not on ALV. However, survival in non-ventilated patients was not recorded in a retrospective cohort study, so it was not possible to compare these endpoints. After 52 weeks of therapy, all 18 patients receiving Mayoim were alive, and 15 of them were alive and not on mechanical ventilation, while in a retrospective cohort study, only 1 in 42 patients were alive at the age of 18 months. Two patients died and did not enter clinical research. After the lapse of 104 weeks of therapy, all 16 patients entering the continuation phase of the clinical study were alive, and 10 of these 16 were not on the ventilator. At the end of the study (the individual duration of patient therapy ranged from 60 to 150 weeks, the average follow-up period was 119 weeks), 14 of 16 patients were alive, and 9 of 16 patients were alive and not on ventilator. One patient died after the end of the study, and the other after his release from the study.
A comparison of the survival curves from the time of the diagnosis of a retrospective group of patients with a natural course of the disease who did not receive therapy was performed using Cox proportional hazard regression analysis. Patients who received Mayoim, demonstrated an increase life expectancy compared with patients who did not receive therapy (see Table 1).
Table 1: Results of the evaluation of the final survival points using the Cox regression model
| Patients, who received treatment | The comparison group data from retrospective study | The ultimate dot | Attitude risks effectiveness of of therapy | 95% confidential interval | R- amount |
| N = 18 | N = 42 | Survival | 0.05 | (0.015, 0.147) | <0.0001 |
Note: Results regression analysis of Cox proportional hazards, including therapy as time-varying covariates, as well as the age at which the diagnosis was made and the age at which the symptoms of the disease appeared.
At the beginning of the study, the patients' age was 6 months or less.
Patients from the retrospective study group who did not receive therapy were born in 1993 and later.
Echocardiography cardiomyopathies have improved, that manifested by a decrease in the mass of the left ventricle (LVH). After 52 weeks of therapy, LVH decreased from all patients in 14 patients and was within normal limits in 3 of these 14 patients. After the first year (64 to 130 pedules) of therapy, LVH also decreased in 8 patients. At the 104th week of therapy, the results of the evaluation of 8 patients were available, of which in 5 cases it decreased to normal limits.
As was determined by points of development of motor functions according to age equivalents of the Scale of development of motor functions in newborns Albert (AIMS), in seven of 18 patients during the study period, development of motor skills, and by the time of the last evaluation in the study, they already went independently (individual the duration of therapy in patients ranged from 52 to 130 weeks; the average follow-up period was 94 weeks). In the other 4 patients in the period the study showed an increase in motor skills, and at the time of the last evaluation conducted in the study, they could already sit on their own (the individual duration of therapy ranged from 78 to 130 weeks, the average follow-up period was 110 weeks), although they functionally used their legs.The remaining 7 patients had no clinically significant improvement in motor skills or were unable to maintain an increase in motor skills, they had a limited number of movements at the time of evaluation at the end of the study (the individual duration of therapy ranged from 52 to 142 weeks, the average follow-up observation was 103 weeks).
After 52 weeks of therapy, in 14 of 18 patients (77.8%), the ratio of body weight to age (above the 3rd percentile) was preserved or improved, in 14 out of 15 (93.3%) they were above the 3rd percentile along the length of the body, and 12 of them 15 (80.0%) they were above the 3rd percentile in terms of the circumference of the head. In the second year of therapy, 15 of 17 patients reported continued improvement in their body-to-age ratio (individual therapy duration ranged from 78 to 142 weeks; the average follow-up period was 111 weeks), 10 of 16 patients had a positive change in the ratio of body-to-age ratio (the individual duration of therapy ranged from 90 to 130 weeks, the average follow-up period was 113 weeks)and 11 of 15 patients had a subsequent improvement in head to age ratio (the individual duration of therapy ranged from 90 to 130 weeks, the average follow-up period was 110 weeks). At the 104th week of therapy, all 13 patients (for which data were available) preserved or improved their body-to-age ratio (above the 3rd percentile), in all 12 patients (data for which there were), the results were higher than the 3rd percentile in body length and in all In 12 patients they were above the 3rd percentile along the circumference of the head.
The efficacy analysis did not reveal significant differences between the 2 dosing groups with respect to survival, survival without exposure to ventilation, and survival without ventilation, and a decrease in LMW. increasing growth rates and acquiring motor skills. Based on these results, a dose of 20 mg / kg is recommended once every two weeks.
Infant form of Pompe disease: a clinical study in patients in ages from 6 months to 3.5 years
The second open clinical trial, also assessing the safety and efficacy of Mayoimine in 21 patients with predominance of an atypical variant of the infantile form of Pompe disease, whose age ranged from 6 months to 3.5 years at the time of initiation of therapy.Patients received Mayoim 20 mg / kg once every two weeks for 52 weeks, except for 8 patients receiving 40 mg / kg after at least 26 weeks of therapy. After 52 weeks, all patients continued treatment, the total duration of which was more than 3 years (168 weeks with a median of 121 weeks).
The primary endpoint in the baseline study was the percentage of surviving patients. After 52 weeks of therapy, 16 of 21 patients (76.2%) who received Mayoim therapy were alive. After 104 weeks of therapy, 14 of 21 patients were alive (66.7%), and 1 patient was alive, but discontinued participation in the study. Such proportions persisted until the end of the study (the individual duration of therapy ranged from 1 to 168 weeks, the average follow-up period was 109 weeks). In the retrospective study group who received therapy. 5 of 47 patients (for whom there were data) (10.6%) were alive at the age of 30 months (2.5 years).
Survival in patients receiving therapy was compared with survival in a similar group of a retrospective study that did not receive therapy using regression analysis of Cox proportional hazards (see Table 2).
Table 2: Results of the endpoint-survival estimate using the regression model
| Patients, who received treatment | The comparison group data from retrospective study | The ultimate dot | Attitude risks effectiveness of of therapy | 95% confidential interval | R- amount |
| N =21 | N = 48 | Survival | 0.301 | (0.112, 0.804) | <0.0166 |
Note: Cox proportional hazard regression analysis results, including therapy as a time-varying covariate, and the age at which the diagnosis was made and the age at which the symptoms of the disease appear.
At the beginning of the study, patients were aged from 6 months to 3.5 years.
Patients from the retrospective study group who did not receive therapy were born in 1995 and later.
Additional efficacy data showed that of 16 patients who were not on an initial level at the initial level, they remained the same after 104 weeks of therapy. The remaining 9 patients either died (5 patients) or were on mechanical ventilation (4 patients). In all 5 patients who had invasive mechanical ventilation at baseline, there was a need for continuation during the whole studies (4 patients remained alive after 104 weeks, 1 died).
After 52 weeks of therapy, LVM decreased from baseline in all 12 patients (for whom data were available) and was within normal limits in 6 of these 12 patients.After the first year (58 to 168 weeks) of therapy, LVH also decreased in 9 of 12 patients (for whom there were data). At 104 weeks of therapy, LVM assessment results were available for only 10 patients, 9 of which fell to norm limits.
After 52 pedal therapies, in 3 out of 8 patients, there was an increase in the development of motor skills compared to the baseline level, which was determined by the initial scores and scores of the age equivalent, but compared with the baseline AIMS.
Six of the 11 patients (for which data were available) continued to improve their motor performance after 52 weeks (the individual duration of therapy varied from 58 to 168 weeks, the average follow-up was 121 weeks), including 3 patients able to walk, and 3 patients, capable only of sitting to the last visit of the study. The remaining 5 patients showed no significant changes in the development of motor skills after 52 weeks (individual PThe duration of therapy ranged from 104 to 168 weeks: the average follow-up period was 140 weeks)including 4 patients with no significant motor skills in any of the evaluated positions and 1 patient who can only sit at the time of the last visit of the study. The vast majority of patients with infantile Pompe disease who received Mayoim therapy showed an improvement in heart function, as well as stabilization and improvement in growth rates. However, the response to treatment with respect to motor activity and respiratory function was more diverse. In patients with infant Pompe disease, who had improved motor skills, the motor function and the lower glycogen content in the quadriceps muscle on the baseline remained to a greater extent. It should be noted that a large proportion of patients with better outcomes for motor activity demonstrated stabilization or improvement in growth (body weight), while in most patients, despite initial characteristics and changes in motor performance, the reverse development of cardiomyopathy was observed Zindicator LMW.
Most of the results showed that early diagnosis and treatment at an early stage of the disease may be critical points for achieving better outcomes in patients with infant Pompe disease.
Pompe disease with late onset; basic clinical study
The safety and efficacy of Mayozyme was evaluated in a randomized, double-blind, placebo-controlled study in 90 patients with late-onset Pompe disease, whose age ranged from 10 to 70 years at the beginning of therapy, all of whom previously received enzyme replacement therapy. Patients were randomized in a 2: 1 ratio and received Mayoim 20 mg / kg (respectively)n= 60) or placebo (n= 30) once every two weeks for 78 weeks (18 months). The combined primary point of effectiveness evaluation was the ability to go through a certain distance (meters) in 6 minutes (test with 6-minute walking, 6MWT) and% of the estimated FVC (forced vital capacity of the lungs) in the sitting position. After 78 weeks, patients who received Mayo demonstrated an improvement in walking distance by distance 6MWT and the stabilization of pulmonary function by the data of% of the prospective FGPL in comparison with patients receiving placebo. The distance traveled in 6 minutes increased by an average of 15.0 meters patients receiving Mayoim, and decreased by an average of 7.5 meters patients who received a placebo, that pointed to the statistical reliability effect of Mayoim compared to placebo (p = 0.0283). % of the estimated FVC has changed by an average of 0.0 patients who received Mayoim. AND decreased by an average of 3% in patients, who received a placebo, pointing to statistical significance of the effect of the therapy (p = 0.0026). results are given in Table 3.
Table 3: Changes compared to baseline: evaluation of efficacy in a placebo-controlled study
|
| Maiozaim (N = 60) | Placebo (N = 30) |
| The distance covered in the 6-minute walk test (meters) |
| Before holding treatment (initial level) | Mean ± RMS Median | 332.20 ± 1 26.69 360.0 | 317.93 ± 1 32.29 339.0 |
| 78 week / last observation
| Mean ± RMS Median | 357.85 ± 1 41.32 367.5 | 313.07 ± 1 44.69 307.0 |
| Changes at 78 weeks the last comparisonYu from initial level * | Mean ± RMS Median | 26.08 ± 64. 41 15.0 | 4.87 ±45.2 4 -7.5 |
| Criterion Wilcoxon- Manna- Whitney | R- amount | 0.0283 |
|
|
|
| The forced vital capacity of the lungs (% of the expected rate) |
|
| Before holding treatment (initialth level) | Mean ± RMS Median | 55.43 ± 14. 44 53.5 | 53.00 ± 15. 66 49.0 |
|
| 78 week / last observed not | Mean ± RMS Median | 56.67 ± 16. 17 55.5 | 50.70 ± 14. 88 49.0 |
|
| Changes at 78 weeks the last observed in comparison with initial level * | Mean ± RMS Median | 1.25 ±5.55 0.0 | -2.3 ±4.33 -3.0 |
|
| Criterion Vnlkokson- Manna- Whitney | R- amount | 0.0026 |
|
| * One patient for whom no data was received after the baseline assessment was excluded from the analyzes. |
|
Pompe disease with late onset; other clinical trials and analyzes
Researchers also conducted three independent, open, uncontrolled studies of Mayozaim:
- One study was conducted in Italy and included 74 patients with late onset of the disease with a follow-up period lasting up to 48 months.
- One study in Germany included 38 patients with a late onset of the disease with a follow-up period lasting 36 months.
- One study was conducted in the Netherlands and included 69 patients with late onset of the disease with a follow-up period lasting up to 23 months. These three studies of Mayoim (with a follow-up period of at least 3 years in two studies and an average of 23 months in another study) demonstrated stabilization or improvement in motor activity and stabilization of respiratory function.
In a study with 69 patients with late onset of the disease.conducted in the Netherlands, the use of Mayoim resulted in an increase in the muscular strength of patients. However, muscle function improved only in patients who are wheelchair-dependent, and in those whose muscle weakness was less pronounced.
Two other open clinical trials of Mayozema with a follow-up period lasting up to 24 months, involving ten patients with severe Pompe disease with late onset (moderate to severe motor disability and mechanical ventilation), showed different responses to the motor function and respiratory function, mainly in the form of moderate improvement (AGLU03105, AGLU04107).
An open clinical trial assessed the efficacy and safety of Mayozyme in 5 patients with late-onset Pompe disease who were between 5 and 15 years old at the time of initiation of therapy (AGLU02804). Patients received Mayoim at a dose of 20 mi/ kg one once every two weeks for 26 weeks. All patients moved freely and all, except for one patient, did not require any respiratory support (1 patient needed non-invasive ventilation at night).Of the 3 patients with significant changes from the lungs at the time of screening / baseline (% of the estimated forced vital capacity in the sitting position ranged from 58 to 67%), two demonstrated clinically significant improvement in FVC (+ 11.5% and + 16.0%) in a sitting position by the 26th week. Evaluation of motor activity gave different results.
Ten patients with progressive Pompe disease with late onset (ie 10/10 dependent on a wheelchair and 9/10 on pulmonary ventilation) at the age of 9-54 years received therapy with alglycosidase alpha at a dose of 20-40 mg / kg once in two
weeks for different periods of time - from 6 months to 2.5 years. Improvements from the lungs noted in patients included apparent improvements in FVC to 35% in one patient, and a significant reduction in the number of hours spent on ventilation in 2 patients. In some patients, there were positive effects of treatment for motor activity, including the restoration of lost motor skills. Only one patient has ceased to be dependent on a wheelchair. In this group of patients, the response rates for motor function also varied.
Register of patients with Pompe disease Doctors and health professionals are advised to register patients with Pompe disease on the site WWW.PomDeReuistrv.com. In this register, anonymous data are collected for patients. The goal of creating a patient register with Pompe disease was to improve the understanding of Pompe disease and monitor the effectiveness of enzyme replacement therapy in dynamics, with the primary goal of improving the clinical outcomes of the disease in these patients.