Clinical Trials

Date: 2017-11-27

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the New Horizons in Fabry Disease Conference

Company: Protalix BioTherapeutics (Israel)

Product: PRX-102 (alpha-galactosidase-A)

Action mechanism:

enzyme replacement therapy. PRX-102 is the Company's proprietary plant cell-expressed, chemically modified recombinant alpha-galactosidase-A enzyme in development as a long-term enzyme replacement therapy (ERT) for the treatment of Fabry disease.

Disease: Fabry disease

Therapeutic area: Rare diseases - Genetic diseases

Country: Australia, Paraguay, Serbia, Spain, UK, USA

Trial details:

The phase I/II clinical trial is a worldwide, multi-center, open label, dose ranging study to evaluate the safety, tolerability, pharmacokinetics and exploratory efficacy parameters of PRX-102 in adult Fabry patients. The trial is designed to enroll 18 adult Fabry patients, each in one of three dosing groups (0.2mg/kg, 1mg/kg and 2mg/kg). Each patient will receive intravenous infusions of PRX-102 every two weeks for 12 weeks. After the completion of the protocol, the Company intends to offer enrolled trial patients the option to continue to receive PRX-102 in an open-label extension study. (NCT01678898)

Latest news:

• On November 27, 2017, Protalix BioTherapeutics announced that positive results from the Company’s Phase I/II open label extension trial of pegunigalsidase alfa, or PRX-102, were presented by Prof. Raphael Schiffmann, Director, Institute of Metabolic Disease at the Baylor Research Institute, Dallas, Texas, at the New Horizons in Fabry Disease Conference. Sixteen male and female adult patients were enrolled in the phase I/II clinical trial across three dosing cohorts (0.2 mg/kg, 1mg/kg and 2mg/kg) and received intravenous infusions of PRX-102 every two weeks. The two-year data includes data from 11 patients enrolled and treated in the long-term open-label extension trial. Patients who did not continue in the extension trial included female patients who became or planned to become pregnant, and therefore were unable to continue in accordance with the study protocol, and patients that relocated to a location where treatment was not available under the clinical study. Regarding efficacy, the following data was recorded at 24 months:
Lyso Gb3 levels decreased approximately 90% from baseline; Renal function remained stable with mean eGRF levels of 108.02 and 107.20 at baseline and 24 months, respectively; An improvement across all the gastrointestinal symptoms evaluated, including severity and frequency of abdominal pain and frequency of diarrhea, were noted; Cardiac parameters, including LVM, LVMI and EF, remained stable with no cardiac fibrosis development detected; In conclusion, an improvement of over 40% in disease severity was shown as measured by the Mainz Severity Score Index (MSSI), a score compiling the different elements of the disease severity including neurological, renal and cardiovascular parameters; and An improvement was noted in each of the individual parameters of the MSSI. Regarding safety, the following data was recorded:
The majority of adverse events were mild to moderate in severity;
During the first 12 months of treatment, only three of 16 patients (less than 19%) formed anti-drug antibodies (ADA), of which two of these patients (less than 13%) had neutralizing antibodies; Importantly, however, the ADAs turned negative for all three of these patients following 12 months of treatment; and The ADA positivity effect had no observed impact on the safety, efficacy or continuous biomarker reduction of PRX-102.
• On September 7, 2016, Protalix BioTherapeutics announced an oral presentation highlighting the results of the phase I/II clinical trial of PRX-102 for the treatment of Fabry disease will be given at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium being held September 6-9, 2016 in Rome, Italy. PRX-102 is a recombinant, plant cell expressed, pegylated, modified version of the human alpha-Galactosidase-A enzyme. The phase I/II clinical trial is an open-label, dose-ranging study designed to treat up to 18 naïve male and female adult patients across three dosing cohorts (0.2 mg/kg, 1mg/kg and 2mg/kg), with intravenous infusions of PRX-102 every two weeks. The clinical results indicate that PRX-102 demonstrated improvements or stabilization across all disease parameters including, plasma Lyso-Gb3, kidney function, cardiac function and pain. Additionally, PRX-102 was well tolerated, with the majority of adverse events being mild and moderate. Currently, all 16 patients enrolled in the phase I/II trial continue to receive 1 mg/kg of PRX-102 in an open label extension trial. The Company is recruiting patients for a phase III pivotal trial of PRX-102 for the treatment of Fabry disease in centers in the United States.
• On August 10, 2016, Protalix BioTherapeutics announced additional positive data from its phase I/II clinical trial of PRX-102 for the treatment of Fabry disease. The efficacy and safety analysis of the phase I/II clinical trial includes data from all 16 enrolled patients (9 male and 7 female) who completed the 12-month treatment period and, of more importance, a subset analysis of 10 patients who met the classic Fabry disease criteria (9 male and 1 female). The classic Fabry patient population is the most common Fabry patient population studied and reported on in the scientific and medical literature, and is the population to be evaluated in the Company’s phase III pivotal trial. Classic Fabry disease is characterized by having less than 30% residual enzyme activity, and typical manifestations involve neurological, skin, ophthalmic and Fabry-specific biomarkers.
Efficacy Results: Improvements or stabilization in efficacy were demonstrated across all disease parameters. Reductions of plasma Lyso-Gb3 ranged from 66.7 to 22.6 ng/ml in all patients and from 102.0 to 33.1 ng/ml in classic patients. Stable kidney function was also observed, as measured by estimated glomerular filtration rate (eGFR), with change from mean eGFR value of 110.78 at base line to 110.23 after 12 months for all patients, and from mean eGFR value of 117.37 to 117.36 for classic patients. All patients had stable cardiac function as measured by left ventricular mass (LVM) and left ventricular mass index (LVMI). The detailed results, as a percentage of change from base line, for both all patients and for the classic Fabry patient subset are presented in the following chart.

% change ±SE	eGFR	LVM	LVMI	Gb3	lyso
All Patients (n=16)	-0.5 ±2.1	-0.0 ±2.5	0.4 ±2.6	-22.2 ± 6.1	-48.9 ± 5.7
Classic Patients (n=10)	-0.1±2.2	-2.6 ±3.4	-3.1 ±3.1	-33.3 ± 7.6	-57.6 ± 6.8

The eGRF data in the foregoing table was measured using the Chronic Kidney Disease Epidemiology Collaboration analysis (CKD-EPI), which is the analysis the Company is using in its phase III pivotal trial of PRX-102, based on discussions with the U.S. Food and Drug Administration. The eGFR slope for all patients (n=16) using CKD-EPI was -2.9 (BL-77.7-156.3). The eGFR slope for classic Fabry patients (n=10) was -1.8 (BL 82.4-156.3). According to a published report, an annualized rate of eGFR change of -3.8 (BL 49-170) was observed in a study of the effect of Fabrazyme on the classic Fabry patient population using CKD-EPI analysis with similar base line of eGFR. The Company’s previously reported interim results for eGFR were analyzed using the MDRD equation, which is an older method and not commonly used in the clinical setting. Using MDRD, the eGFR slope is -3.25 for all patients (previously reported as -0.32), and -1.70 for classic patients.
PRX-102 also demonstrated, using the well-established BPI index, a substantial improvement in all pain parameters for all patients in the study, and an even more pronounced improvement in classic Fabry patients, as indicated below:

	Worse Pain	Average Pain	Pain Interference
All Patients	-29 %	-26 %	-39 %
Classic Fabry Patients	-38 %	-41 %	-44 %

Safety Results: The safety analysis for adverse events represents a total of 26.2 patient years. PRX-102 was well tolerated, with the majority of adverse events being mild and moderate. Only one of the patients evaluated for safety experienced hypersensitivity. Only three patients developed antibodies and, after competing 12 months of treatment, one of those three patients has now tested negative for antibodies further supporting the potential of an immune tolerance phenomenon associated with the PRX-102 enzyme. Accordingly, the previously reported 19% incidence of treatment-induced anti-drug antibodies is now only 13%. Moreover, titers of the other two positive patients that developed antibodies have continued to decline over time.
Currently, all 16 patients enrolled in the trial continue to receive 1 mg/kg of PRX-102 in an open label extension trial. The Company is recruiting patients for the phase 3 pivotal trial in centers recently opened in the United States.
* On October 19, 2015, Protalix BioTherapeutics announced positive long term data from the 0.2mg, or lowest dose, of the Company's phase I/II dose ranging clinical trial of PRX-102 for the treatment of Fabry disease. The phase I/II clinical trial of PRX-102 for the treatment of Fabry disease is an open-label, dose-ranging study treating up to 18 naïve male and female patients. The three dose cohorts include dosage groups of 0.2 mg/kg, 1mg/kg and 2mg/kg with intravenous infusions of PRX-102 every two weeks. The data presented herein is from patients in the 0.2mg/kg dose group following 12 months of treatment.
Clinical Data on Kidney Functions: Among the leading causes for death of Fabry patients include renal failures. On average, patients that participated in the 0.2mg/kg cohort of the PRX-102 trial exhibited stability in kidney function with favorable trends shown, as measured by estimated Glomerular filtration rate (eGFR). In a typical Fabry patient, the eGFR deteriorates over time, showing that kidney function is worsening. After dosing with 0.2mg/kg of PRX-102 for 12 months, a majority of the patients (4/6) experienced a stabilization or improvement in kidney function; a reversal of the decline shown by annualized eGFR slope was observed.
Detailed Clinical Data on Other Biomarkers and Scales: Lyso-Gb3 is a sensitive and reliable biomarker of Fabry disease. It is used as a biomarker as it dramatically increases and accumulates in the plasma of Fabry patients. Throughout the study, continuous and durable reduction of up to 61.8% of plasma lyso-Gb3 levels from base line was observed in patients in the 0.2mg/kg cohort. This represents a meaningful positive outcome of PRX-102 treatment.
In addition, Fabry patients of the 0.2mg/kg cohort of the PRX-102 trial showed a continuous reduction and durable improvement in Mainz Severity Score Index (MSSI), a tool for disease status evaluation of a variety of signs and symptoms of Fabry disease including cardiovascular, renal and neurological.
Pharmacokinetics: PRX-102 PK properties resulted in long half-life, high AUC and measured levels of enzyme found throughout the entire two weeks infusion intervals in all patients of the 0.2mg/kg cohort of the trial, potentially contributing to an immune tolerance phenomenon. This resulted in low incidence of antibody formation with low titers in general, and moreover, in antibody positive patients it resulted in a transient and reversible shift of overall drug availability. Mean values for Cmax, and AUC were found to have briefly shifted at three and six months in antibody positive patients, where at 12 months, PK parameters returned to the high AUC levels observed at baseline, demonstrating that the antibody presence and its impact was transient, leading to full active dose availability for effective treatment. In addition, PRX-102 continues to be well tolerated with a favorable safety profile, with the majority of adverse events being mild and moderate in severity with a very low rate of antibody formation.
Protalix Biotherapeutics has scheduled an end of phase II meeting with the FDA to be held during the month of November to discuss the design of the pivotal phase III trial which the Company expects to start in early 2016.
• On September 9, 2015, Protalix BioTherapeutics announced positive interim data from the Company's phase I/II clinical trial of 1mg/kg of PRX-102 for the treatment of Fabry disease. The phase I/II clinical trial of PRX-102 for the treatment of Fabry disease is an open-label, dose-ranging study treating up to 18 naïve male and female adult patients. The three dose cohorts include dosage groups of 0.2 mg/kg, 1mg/kg and 2mg/kg with intravenous infusions of PRX-102 every two weeks, with a six-month efficacy follow up period. This interim analysis includes 6 patients enrolled in the 1mg/kg dose group at six months of treatment. The interim safety analysis includes 18 patients enrolled in three dose cohorts of 0.2mg/kg, 1mg/kg and 2mg/kg.
Interim Efficacy Results: Based on an analysis of kidney biopsies with randomized blinded scoring (n=4), PRX-102 demonstrated a reduction in renal peritubular capillary Gb3 of 86% using a quantitative Barisoni Lipid Inclusion Scoring System (BLISS). Reductions of plasma Lyso-Gb3 and plasma Gb3 concentrations were also observed. Males (n=4) demonstrated a -67.5 ng/mL and a -5.3 µg/mL change, Females (n=2) demonstrated a -9.2 ng/mL mean change in Lyso-Gb3 and a -0.23 µg/mL mean change in plasma Gb3, respectively. Furthermore, all patients had stable cardiac function after only six months, as measured by left ventricular mass (LVM), left ventricular mass index (LVMI) and ejection fraction (EF). Stable kidney function was also observed, as measured by estimated glomerular filtration rate (eGFR) and urine protein.
Safety Results: The safety analysis for adverse events represents a total of 15 patient years. PRX-102 was well tolerated, with the majority of adverse events being mild and moderate. Only one of the patients evaluated for safety experienced hypersensitivity, and only three patients, or approximately 19%, developed antibodies.
Enrollment in the phase I/II clinical trial of PRX-102 was completed in early February 2015. All patients that completed the trial opted to continue to receive PRX-102 in an open-label extension study. The Company expects to report longer term data of the first 0.2mg/kg cohort by the end of this month and to report full top-line results from all dosing cohorts in the fourth quarter of 2015. The Company scheduled an End of Phase II meeting with the Food and Drug Administration before year-end to discuss the design of the pivotal phase III trial, which the Company expects to start in early 2016.
* On February 12, 2015, Protalix BioTherapeutics announced that additional positive interim data from the Company's phase I/II dose-ranging clinical trial of PRX-102 for the treatment of Fabry disease will be presented at the Lysosomal Disease Network WORLD Symposium in Orlando. Dr. Ozlem Goker-Alpan, Director of the Lysosomal Disorders Unit, O&O Alpan LLC, Springfield, Virginia, USA, and principal investigator in the clinical trial, will be presenting interim results from the global, open-label, phase I/II dose-ranging trial. In the trial, 18 naïve male and female patients (11 male and 7 female) were enrolled across three dosing cohorts of 0.2 mg/kg, 1mg/kg and 2mg/kg for which intravenous infusions were administered every two weeks, with a six-month initial efficacy follow-up period.
Pharmacokinetics: PRX-102 has a significantly longer circulatory half-life (T½) of approximately 60 hours, and a substantially higher area under the curve (AUC) of approximately 70,000 ng/mL*hour for the 0.2mg/kg dose, when compared to currently marketed enzyme replacement therapies. These enhanced pharmacokinetic benefits are believed to be the result of the chemical modifications made to PRX-102, including cross-linking and covalent bonding to make the enzyme a more stable homo-dimer. The table below details the full pharmacokinetic profile of PRX-102.

Dose (mg/kg)	T½ (hr)	Tmax (hr)	Cmax (ng/mL)	AUC 0-? (ng/mL*hr)
0.2	58.63 ±16.08	4.40 ±0.56	1858 ±531	69996 ±25904
1	73.76 ±10.89	5.16 ±1.38	10228 ±1812	373975 ±35490

The interim efficacy analysis includes 6 patients enrolled in the 0.2mg/kg dose group at six months of treatment (for Gb3 in renal peritubular capillaries n=5). The interim safety analysis includes 12 patients; 6 patients enrolled in the 0.2mg/kg dose group and 6 patients enrolled in the 1mg/kg dose group.
Clinical Data on Cardiac and Kidney Functions: The leading causes for death of Fabry patients include cardiovascular disease and renal failures. All patients that participated in the trial exhibited stable cardiac and kidney function with favorable trends after only six months of treatment, as measured by mean left ventricular mass (LVM), left ventricular mass index (LVMI), ejection fraction (EF), estimated Glomerular filtration rate (eGFR) and urine protein.The table below sets forth the mean absolute values, at baseline and after six months of treatment, and including percentage changes, which were scored in a randomized blinded manner.

Timeframe	LVM (gr)	LVMI (gr/m2)	EF (%)	eGRF (mL/min/1.73m2)	Urine Protein (mg/g creatinine)
Baseline	98.0	55.1	55.1	109.1	186.3
6 Months	94.4	52.7	55.8	115.8	167.8

Detailed Clinical Data on All Other Disease Parameters: Based on an analysis of kidney biopsies with randomized blinded scoring, PRX-102 demonstrated a major reduction from baseline in renal peritubular capillary Gb3 using both the quantitative Barisoni Lipid Inclusion Scoring System (BLISS) and the semi quantitative method. Using the BLISS method, a reduction in the rate of 82.2% for males, 65.4% for females and 75.5% for males and females combined were observed. Absolute change from baseline was -4.5, -1.2 and -3.2, respectively. Applying the semi quantitative scoring method, commonly used by approved enzyme replacement therapies, PRX-102 demonstrated a reduction of 69.6% in abnormal capillary score.
Patient Data for BLISS Score Analysis:

Patient	Absolute Change from Baseline	Percentage Change from Baseline
F101 (F)	-2.0	-76.9
F102 (F)	-0.4	-52.9
F103 (M)	-3.0	-91.7
F104 (M)	-5.3	-86.2
F106 (M)	-5.3	-69.5

Using the well-accepted Brief Pain Inventory scale, a 100% reduction in pain at its worst, a 60.0% reduction in mean severity, and 78.8% reduction on mean interference (which includes walking, working, sleeping, enjoyment of life and others) were observed. In addition to a 100% reduction in worst pain, all patients also reported a 100% reduction in mean interference, with the exception of one patient who experienced a 33.3% reduction.
Reductions of plasma Lyso-Gb3 and plasma Gb3 concentrations were also observed. Females (n=2) demonstrated a -2.4 ng/mL mean change in Lyso-Gb3 and a -0.4 µg/mL mean change in plasma Gb3. Males (n=4) demonstrated a -96.2 ng/mL and a -1.3 µg/mL change, respectively. All patients demonstrated a reduction in absolute Lyso-Gb3 concentration and all patients demonstrated a reduction in Gb3 except for one patient.
A meaningful reduction in the total score of Mainz Severity Score Index (MSSI), which looks at general, neurological, cardiovascular and renal parameters, was also demonstrated, with a reduction in all parameters included in MSSI.
The safety analysis for adverse events represents a total of 6.7 patient years (n=12). PRX-102 was well tolerated, with the majority of events being mild and moderate. Only 1 of the 12 patients evaluated for safety experienced hypersensitivity and discontinued per protocol. For this patient, anti PRX-102 IgG was negative and anti PRX-102 IgE was positive at baseline.
Six patients receiving the 0.2mg/kg dose and 2 patients receiving the 1mg/kg dose were evaluated for anti-drug antibody formation after six and three months of treatment, respectively. Of these 8 patients, only 2 patients, both in the 0.2 mg/kg dose cohort, developed anti-drug antibodies. All adverse events experienced by these patients were deemed by the investigators to be unrelated to the drug.
Enrollment in the phase I/II clinical trial of PRX-102 was completed in early February. All patients that completed the trial opted to continue to receive PRX-102 in an open-label extension study. The Company expects to report interim results from the 1mg/kg cohort in the third quarter of 2015, and full top-line results from all dosing cohorts in the fourth quarter of 2015.
• On February 2, 2015, Protalix BioTherapeutics announced that the Company has completed enrollment in its phase I/II clinical trial of PRX-102 for the treatment of Fabry disease. All patients that completed the trial have opted to continue to receive PRX-102 in an open-label extension trial. On February 12, 2015 at 10:45AM ET Dr. Ozlem Goker-Alpan, President and Chief Medical Officer of the Center for Clinical Trials, O&O Alpan, LLC., and Director of the Lysosomal Research and Treatment Unit, will present interim results from the phase I/II trial in an oral presentation titled, "Novel treatment for Fabry disease, IV administration of plant derived ?-GAL-A enzyme phase 1/2 safety and efficacy study: interim clinical report" at the Lysosomal Disease Network WORLD Symposium in Orlando, FL.
Additionally, the Company expects to report interim results from the 1mg/kg cohort in the third quarter of 2015, and full top-line results from all dosing cohorts in the fourth quarter of 2015. Management will request an end of Phase II meeting with the U.S. Food and Drug Administration in the fourth quarter of 2015, and anticipates initiating a phase III pivotal trial in early 2016.
The phase I/II clinical trial of PRX-102 is an open-label, dose-ranging study treating 18 naïve male and female patients with Fabry disease. The three dose cohorts include dosage groups of 0.2 mg/kg, 1mg/kg and 2mg/kg with intravenous infusions of PRX-102 every two weeks, with a six-month efficacy follow up period.
• On January 8, 2015, Protalix BioTherapeutics announced positive interim efficacy and safety data from the Company's ongoing phase I/II clinical trial of PRX-102 for the treatment of Fabry disease. PRX-102 demonstrated meaningful clinical benefits across the following key disease parameters already in the low dose of 0.2 mg/kg:Major reduction in Gb3 in Renal Peritubular Capillaries, Significant improvement in all pain parameters, Stabilization of cardiac and kidney function with favorable trends, Low level of antibody formation. The phase I/II clinical trial of PRX-102 for the treatment of Fabry disease is an open-label, dose-ranging study treating up to 18 naïve male and female patients. The three dose cohorts include dosage groups of 0.2 mg/kg, 1mg/kg and 2mg/kg with intravenous infusions of PRX-102 every two weeks, with a six-month efficacy follow up period.
The interim efficacy analysis includes 6 patients enrolled in the 0.2mg/kg dose group at six months of treatment (for Gb3 in renal peritubular capillaries n=5). The interim safety analysis includes 12 patients; 6 patients enrolled in the 0.2mg/kg dose group and 6 patients enrolled in the 1mg/kg dose group.
Interim Efficacy Results:Based on an analysis of kidney biopsies with randomized blinded scoring, PRX-102 demonstrated a reduction in renal peritubular capillary Gb3 of 82.2% for males and 65.4% for females using a quantitative Barisoni Lipid Inclusion Scoring System (BLISS) for a combined reduction of 75.5%. Applying the semi quantitative scoring method, commonly used by approved enzyme replacement therapies, PRX-102 demonstrated a reduction of 69.6% in abnormal capillary score. Using the well-accepted Brief Pain Inventory scale, a 100% reduction in Worst Pain and an average of 78.8% improvement on patients' Impact On Functioning were observed. Furthermore, all patients had stable cardiac function, with favorable trends after only six months, as measured by left ventricular mass (LVM), left ventricular mass index (LVMI) and ejection fraction (EF). Stable kidney function was also observed, with favorable trends after only six months, as measured by estimated glomerular filtration rate (eGFR) and urine protein.
Safety Results: The safety analysis for adverse events represents a total of 6.7 patient years. PRX-102 was well tolerated, with the majority of events being mild and moderate. Only one of the 12 patients evaluated for safety experienced hypersensitivity. Six patients receiving the 0.2mg/kg dose and 2 patients receiving the 1m/kg dose were evaluated for antibody formation. Of these 8 patients, only 2 patients, or 33% of the 0.2 mg/kg dose cohort, developed antibodies.
"The safety and clinical benefits of PRX-102 demonstrated in the interim results are extremely exciting and promising. Meaningful improvement or stability was seen across all disease parameters studied, including Gb3 levels, renal function, pain and cardiac parameters," said Professor Raphael Schiffmann, Director, Institute of Metabolic Disease at the Baylor Research Institute, Dallas, Texas, and a principal investigator in the PRX-102 clinical trial. "The safety profile reported is favorable, with most adverse events mild to moderate and transient in nature. The potential to treat patients with an improved alternative of enzyme replacement therapy would be a significant advance in the treatment of Fabry disease."
Dr. Derralynn Hughes of the Lysosomal Storage Disease Unit, Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK, and a principal investigator in the PRX-102 clinical trial commented, "These interim results provide very encouraging efficacy and safety data with PRX-102, a plant-cell expressed alpha-GAL-A, in Fabry patients. Of particular note are the meaningful reductions in pain and renal Gb3 levels and favorable safety profile. Fabry disease is a rare, life-threatening condition for which there is a clear need for alternative treatment options."
Currently, patients are being treated in all three dose groups of the Phase I/II trial, and the Company expects to conclude enrollment by the end of first quarter of 2015. All patients that have completed the initial six-month efficacy follow-up have opted to be enrolled in the extension studies. The Company is planning to present additional interim results at the WORLD symposium which is being held February 9-13, 2015 in Orlando, Florida. Efficacy results for the 1mg/kg dosing cohort are expected to be announced in the third quarter of 2015 and full trial results are anticipated in the fourth quarter of 2015.
• On December 10, 2012, Protalix BioTherapeutics has announced that the first patient has been treated in its phase I/II clinical trial of Fabry patients with PRX-102.
• On August 13, 2012, Protalix BioTherapeutics has announced that it has received clearance of its Investigational New Drug (IND) application from the FDA to initiate clinical trials of PRX-102. The Company plans to commence enrollment of Fabry disease patients for a phase I/II trial in the fourth quarter of 2012.

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