Date: 2018-06-26
Type of
information: Interim results
phase: 1-2
Announcement: interim results
Company: Amicus Therapeutics (USA - NJ)
Product: AT-GAA (ATB200/AT2221)
Action
mechanism:
- enzyme replacement therapy. ATB200 is an engineered recombinant human acid alpha-glucosidase (rhGAA) enzyme with an optimized carbohydrate structure, administered in combination with a small molecule pharmacological chaperone (AT2221). In preclinical studies, ATB200 was associated with increased tissue enzyme levels and reduced substrate, which was further improved when AT2221 was co-administered with ATB200.
Disease: Pompe disease
Therapeutic
area: Genetic diseases - Rare diseases - Metabolic diseases
Country: Australia, Germany, Netherlands, UK, USA
Trial
details:
- This study is an international, multi-center, study of Pompe disease patients that are currently receiving enzyme-replacement therapy (ERT). The purpose of this study is to find out if the co-administration of investigational new drugs ATB200 and AT2221 is safe in adults with Pompe disease.
- • Primary objectives: to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATB200/AT2221 • Study duration: 18-week primary treatment period followed by a long-term extension
- • Patient cohorts: ambulatory ERT-switch patients (Cohort 1), non-ambulatory ERT-switch patients (Cohort 2) and ERT-naïve patients (Cohort 3). Enrolling up to ~20 total patients across all cohorts. (NCT02675465)
Latest
news:
- • On June 26, 2018, Amicus Therapeutics announced regulatory and clinical advancements in its development program for AT-GAA for Pompe disease following guidance from regulators in the European Union as well as guidance on manufacturing and bio-comparability from German regulatory authorities (BfArM).
- Regulatory & Clinical: During the second quarter, Amicus met with the Scientific Advice Working Party (SAWP) within the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). The purpose of the discussions were two-fold:
- 1) to gain alignment on the design of a pivotal study for full approval for AT-GAA as well as other supplemental clinical studies in Pompe patients;
- 2) to discuss whether Amicus may pursue a pathway for AT-GAA that includes a conditional marketing approval (CMA) application in Europe. Amicus has concluded this series of interactions and has now received written guidance from the SAWP.
- With respect to the pivotal study, Amicus will incorporate SAWP feedback on key elements of the nature and design of the pivotal study. The pivotal study is planned to focus on up to 80 ERT-switch patients with 6-minute walk as the primary endpoint and a primary treatment period up to 12 months. Patients enrolled in the current prospective observational study being conducted by Amicus (STRIDE Study 003) would be entered into the pivotal treatment study. This pivotal study is expected to commence in 2H 2018, pending feedback from the Type C meeting with FDA which is on track for 3Q18.
- The SAWP was also supportive of studying additional patient populations, including pediatric Pompe patients and ERT-treatment naïve Pompe patients. Amicus expects to include these patient populations in studies to initiate in 2019, in addition to the pivotal study in ERT-switch patients. With respect to a pathway for conditional approval, while the SAWP specifically noted that the efficacy data for AT-GAA to date appear “promising” the SAWP indicated that the current clinical package is not sufficient for a Conditional Marketing Authorization Application at this time. Amicus intends to continue a dialogue on a potential pathway for conditional approval with the EMA authorities in 2019 with further data on both efficacy and safety to include:
- *Data from up to 10 additional ERT-switch patients in a new Cohort 4 as part of the ongoing Phase 1/2 study (data expected in 2019)
- *Presentation of longer-term clinical data out to 18-months for the 19 original Phase 1/2 patients (data expected in 2H 2018)
- *Completion of a retrospective natural history study in approximately 100 ERT-treated Pompe patients (data expected in 2H 2018)
- As the clinical data continue to develop, Amicus will also be able to commence the Process Performance Qualification (PPQ) runs at the 1,000 Liter (commercial scale). These PPQ manufacturing runs will be essential for any marketing application under any pathway in both the EU and United States.Manufacturing Comparability: In a separate meeting with the German regulatory authorities (BfArM), Amicus received scientific advice indicating general agreement with the manufacturing strategy for ATB200, including on the strategy to demonstrate comparability between drug substance and drug product manufactured at the 1,000 liter scale and drug substance and drug product manufactured at the 250 liter scale. Amicus Therapeutics now looks forward to the Type-C meeting with FDA on this program in the third quarter and to incorporating their feedback along with that of the CHMP to initiate the pivotal trial this year.
- • On May 15, 2017, Amicus Therapeutics announced positive functional data from initial patients in a global Phase 1/2 study (ATB200-02) to investigate ATB200/AT2221 in patients with Pompe disease. Patients who completed six months of treatment with ATB200/AT2221 showed improvements in the six-minute walk test (6MWT) distance and other measures of motor function, in addition to stability or improvements in forced vital capacity (FVC). Consistent with previous results1 presented at the 2017 WORLDSymposium™, patients treated with ATB200/AT2221 continue to show improvements in biomarkers of muscle damage and disease substrate.
- ATB200-02 Study - Updated Data Highlights in Initial ERT-Switch and Naive Patients:*Safety, Tolerability & Pharmacokinetics (PK): Safety and tolerability data are currently available for all 20 patients enrolled in the study (maximum 48 weeks). To date, adverse events have been generally mild and transient. Importantly, ATB200/AT2221 has also shown no infusion-associated reactions following 200+ infusions. As previously reported, the clinical PK profile has been consistent with previously reported preclinical data.*Pharmacodynamic (PD) Data on Muscle Damage and Disease Substrate Biomarkers (n=16)
PD data are currently available for 11 ERT-switch patients and five ERT-naïve patients. Improvements in key biomarkers of muscle damage and disease substrate continue to suggest a positive effect of ATB200/AT2221 on muscle cells after up to 34 weeks of treatment.
- Muscle damage biomarkers: Creatine kinase (CK) enzyme, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) continue to show a decrease in a majority of patients. Across the three biomarkers, mean reductions from baseline were approximately 15-20% and 50-55% for the ERT-switch and ERT-naïve patients, respectively.Disease substrate biomarker: Urine hexose tetrasaccharide (Hex4) continues to show decreases in a majority of ERT-switch patients and all ERT-naïve patients, with mean reductions from baseline of approximately 40% and 50% for the ERT-switch and ERT-naïve patients, respectively.
- *Functional Outcomes at Month 6 (n=10)
Functional outcomes data from baseline to Month 6 are currently available for 10 patients (seven ambulatory ERT-switch, two ERT-naïve and one non-ambulatory ERT-switch). Motor function improved and pulmonary function was stable in ambulatory ERT-switch patients; motor and pulmonary function both improved in ERT-naïve patients. Muscle strength data are available from the first non-ambulatory ERT-switch patient and showed improvement.Muscle Function:
- Motor function: Six-minute walk test (6MWT) distance, a primary measure of motor function in Pompe patients, increased in both ERT-switch patients (mean +38 meters; improvement in 6/7 patients) and ERT-naïve patients (mean +52 meters; improvement in 2/2 patients). Other motor function tests also showed mean improvements, consistent with 6MWT distance.- Muscle Strength: In the first non-ambulatory ERT-switch patient, improvements in four out of four muscle groups on the quantitative muscle testing (QMT) and two of three muscle groups on the manual muscle testing (MMT) were observed.Pulmonary Function: Forced vital capacity (FVC), the primary measure of pulmonary function, was stable in ERT-switch patients (mean absolute change in percent predicted FVC +0.3%) and improved in ERT-naïve patients (mean absolute change +3.0%). Other pulmonary tests included maximal inspiratory pressure (MIP), a measure of inhalation, and maximal expiratory pressure (MEP), a measure of exhalation. MIP and MEP both showed mean increases in ERT-switch patients. MIP showed a mean increase and MEP showed a mean decrease in ERT-naïve patients.Summary of Functional Outcomes from Baseline to Month 6:
-
|
| Cohort 1 ERT-Switch Patients (n=7): Functional Outcomes on ATB200/AT2221 from Baseline to Month 6 |
| |
Motor Function Tests (n=7) |
Pulmonary Function Tests (n=6-7) |
| |
6MWT (m) |
4 Stair
Climb (sec) |
Timed up
and go (sec) |
10m walk
(sec) |
FVC (%) |
MIP |
MEP |
| Baseline
Mean (SD) |
383 (103) |
4.4 (3.1) |
11.0 (7.7) |
7.5 (3.5) |
51 (17) |
35.4 (11.3) |
69.5 (21.2) |
| Change from
Baseline (SD) |
+38 (43) |
-1.1 (1.3) |
-1.9 (2.8) |
-0.04 (1.6) |
+0.3 (3) |
+1.0 (5.2) |
+15.5 (25.4) |
|
| Cohort 3 ERT-Naïve Patients (n=2): Functional Outcomes on ATB200/AT2221 from Baseline to Month 6 |
| |
Motor Function Tests (n=2) |
Pulmonary Function Tests (n=2) |
| |
6MWT (m) |
4 Stair
Climb (sec) |
Timed up
and go (sec) |
10m walk
(sec) |
FVC (%) |
MIP |
MEP |
| Baseline
Mean (SD) |
432 (68) |
3.9 (0.6) |
8.9 (0.9) |
6.9 (0.8) |
51 (27) |
45.5 (27.6) |
57.5 (9.2) |
| Change from
Baseline (SD) |
+52 (15) |
-0.3 (0.0) |
-1.4 (0.4) |
-0.5 (0.2) |
+3 (0) |
+8.5 (3.5) |
-4.5 (17.7) |
- • On February 15, 2017, Amicus Therapeutics presented additional positive preliminary data from a global Phase 1/2 study (ATB200-02) to investigate ATB200/AT2221 in a poster1 at the 13th Annual WORLDSymposium™ in San Diego, CA. Preliminary data now available include safety data for 13 patients through interim data analysis (maximum 36 weeks) and PK and PD (muscle biomarker and disease substrate biomarker) data for 10 patients (eight ERT-switch patients and two naïve patients). ATB200/AT2221 safety measures (n=13) showed no serious adverse events (SAEs). TEAEs were generally mild and transient. To date, ATB200/AT2221 has shown no infusion-associated reactions following 150+ infusions. Clinical PK profile was consistent with previously reported preclinical data (n=10). ATB200 plasma clearance suggests optimized carbohydrate structure provides efficient uptake into tissues.ATB200 exposure was further enhanced with the addition of the chaperone AT2221, consistent with stabilization of ATB200 by AT2221. Reductions observed in biomarkers of muscle damage (creatine kinase (CK) enzyme, alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) in ambulatory switch patients (N=8, week 18) and naïve patients (N=2, week 4). In the eight ERT-switch patients:
- • ALT decreased in 5 of 8 patients; 4/4 patients with elevated baseline levels normalized
- • AST decreased in 6 of 8 patients; 3/4 patients with elevated baseline levels normalized
- • CK decreased in 6 of 8 patients; 2/6 patients with elevated baseline levels normalized
- • ALT, AST, CK generally remained stable in patients not demonstrating a decrease
- • In the two ERT-naïve patients, all three biomarkers improved
- • Reduction observed in a biomarker of glycogen substrate -- Urine Hexose Tetrasaccharide (Hex4) -- in all eight ERT-switch patients and both naïve patients; overall reduction approximately 30%
- • On December 22, 2015, Amicus Therapeutics announced that its investigational new drug (IND) application, submitted to the FDA, is now effective which allows Amicus to begin site initiation and enrollment of a Phase 1/2 study of ATB200 in patients with Pompe disease. Amicus intends to seek regulatory authorization to evaluate ATB200 in European patients as well. Amicus Therapeutics is looking forward to seeing data from the study in 2016.
- • On February 10, 2015, Amicus Therapeutics highlighted results from preclinical studies of its next-generation Pompe ERT (Enzyme Replacement Therapy) at WORLDSymposium 2015 in Orlando, Florida. Amicus is leveraging its biologics capabilities and CHART™ (Chaperone-Advanced Replacement Therapy) platform to develop a next-generation Pompe ERT. This ERT consists of a uniquely engineered recombinant human acid alpha-glucosidase (rhGAA) enzyme (designated ATB200) with an optimized carbohydrate structure to enhance uptake, administered in combination with a pharmacological chaperone to improve activity and stability. In earlier preclinical studies, ATB200 demonstrated greater tissue enzyme levels and further substrate reduction compared to the current approved ERT for Pompe disease (alglucosidase alfa). Clinical studies of pharmacological chaperones in combination with currently marketed ERTs have established initial human proof-of-concept that a chaperone can stabilize enzyme activity and potentially improve ERT tolerability. A proprietary cell line and manufacturing processes have been developed to produce ATB200 with optimized carbohydrate structures for efficient cellular uptake and lysosomal targeting. ATB200 has been successfully scaled up to 250L production, and is on track to enter the clinic in the second half of 2015.
- ATB200 was significantly better than the approved ERT for reducing disease substrate in multiple key muscle tissues in a Pompe animal model (Gaa knock-out mice) The addition of a pharmacological chaperone further improved glycogen reduction by ATB200
Is
general: Yes
