Pompe-DiseaseNCT05448131
ERT in Pompe Disease: Elucidation of Molecular Structures Contributing to Enzyme Uptake and Immunoreactivity
An observational study of Pompe-Disease, run by Centre for Analytical Biochemistry and Biomedical Mass Spectrometry at 1 site in Germany.
Trial summary
In the first part of this study, the aim is to characterize the molecular structure of wildtype GAA and, in particular, of mutated GAA variants with and without HSAT, in order to learn how mutation impairs uptake of GAA into the cell via the M6P receptor. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Pompe-Disease
- How many people
- 50 participants
- Where
- 1 siteGermany
- Study dates
- 1 Feb 2023to 7 Oct 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: 50 patients who meet all eligibility criteria will be enrolled in the study.
Who may be able to join
- All patients or their legal guardian and healthy volunteers with normal GAA enzyme activity and genotype will give informed consent to participate in this explorative, cross-sectional study.
- IOPD/LOPD patients will have a confirmed diagnosis of Pompe disease based on enzyme activity reduction and genetic GAA mutations.
- Both CRIM-positive and CRIM-negative IOPD patients will be included.
- Patients with IOPD/LOPD will be on enzyme replacement therapy on their individual treatment regime.
- Healthy volunteers will be included as controls for wildtype GAA analysis.
Who cannot join
- Patient/healthy volunteer or legal guardian do not agree to give informed consent.
- The patient/healthy volunteer is not capable to adhere to the study protocol.
- The patient is not treated with enzyme replacement therapy.
Trial locations and contacts
1 site in 1 country.
Germany1 site, 1 recruiting
- Recruiting
Centre for Analytical Biochemistry
Rüsselsheim am Main, Hesse, 65428
Michael Przybylski, PhD, +49 6142 8345511, michael.przybylski@stw.de
Loredana Lupu, PhD, +49 6142 8345512, loredanalupu92@gmail.com
About this study
Official title: Towards an Individually Tailored Enzyme Replacement Therapy in Pompe Disease: A Controlled Study for Elucidation of Molecular Structures Contributing to Enzyme Uptake and Immunoreactivity
In the first part of this study, the aim is to characterize the molecular structure of wildtype GAA and, in particular, of mutated GAA variants with and without HSAT, in order to learn how mutation impairs uptake of GAA into the cell via the M6P receptor. In the second part of the study the aim is to learn to which epitopes antibodies bind and to which not. To accomplish this the investigators will synthesize and chemically modify the epitope peptides, in order to block effectively antibodies directed against the therapeutic enzyme.
Read the detailed description
Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA = alglucosidase alfa) is available since 2006, and has been shown effective in IOPD and LOPD; however the treatment response is variable and imperfect. This has prompted the development of a next-generation rhGAA with increased glycosylation and improved muscle cell uptake (avalglucosidase alfa). The efficacy of ERT significantly depends on the glycosylation status of the enzyme determining muscle cell uptake via the mannose-6-phosphate (M6P) receptor, and on the formation of antibodies directed against the recombinant enzyme. The impact of immunological factors on efficacy is highlighted by the occurrence of high sustained antibody titers (HSAT) in IOPD patients producing no GAA at all (CRIM-negative), that result in a worse outcome similar to that of untreated patients, if no immunomodulating medication is given. Such HSAT can also occur in IOPD patients synthesizing a non-functional GAA (CRIM-positive) and in some late onset Pompe Disease (LOPD) patients.
In the first part of this study, the investigators aim to characterize the molecular structure of wildtype GAA and, in particular, of mutated GAA variants with and without HSAT, in order to learn how mutation impairs uptake of GAA into the cell via the M6P receptor. To accomplish this, 5 healthy subjects and 45 Pompe disease patients will be studied (15 IOPD and 30 LOPD). The investigators will identify antibody epitopes in the sera of patients with rhGAA antibodies and determine and compare quantitatively their binding affinities, by using a combination of proteolytic affinity-mass spectrometry and surface plasmon resonance biosensor analysis. The investigators reason that specific mutations may affect the epitope status differently. Related to this, the investigators also speculate that glycosylations and M6P residues could modify epitopes in their close vicinity. These results will help to understand where the antibody binding epitopes are located.
In the second part of the study the investigators aim to learn to which epitopes antibodies bind and to which not. To accomplish this the epitope peptides will be synthesized and chemically modified, in order to block effectively antibodies directed against the therapeutic enzyme. Applying high affinity GAA epitope peptides capable of binding neutralizing antibodies is expected to potentially improve efficacy and safety of ERT, thereby providing a new targeted and personalized immunotolerance approach.
- Conditions
- Pompe-Disease
- Keywords
- Antibodies
- Medical subject headings
- Glycogen Storage Disease Type II
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of epitope numbers of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies
Epitope numbers of wtGAA, rhGAA, and mutated GAAs will determine the number of Pompe patients with polyclonal and monoclonal antibodies, and determine whether specific antibodies are more prevalent than others among Pompe patients.
Measured: Only at baseline visit
Determination of epitope locations of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies
Epitope locations of wtGAA, rhGAA, and mutated GAAs will determine the number of Pompe patients with polyclonal and monoclonal antibodies, and determine whether specific antibody epitopes are more prevalent than others among Pompe patients.
Measured: Only at baseline visit
Determination of epitope- specific affinities of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies
Epitope- specific affinities of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies in PD patients will be determined for correlation with mutations in GAA structure
Measured: Only at baseline visit
Secondary outcomes (2)
Determination of the number of PD patients with specific neutralizing antibody epitopes
Neutralizing antibodies in PD patients may be differentiated by their epitope specificities.
Measured: Only at baseline visit
Determination of antibody titers in PD patients
Determination of epitope-specific antibody titers
Measured: Only at baseline visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jul 2022
- Study start1 Feb 2023
- Primary completion6 Aug 2024 (estimated)
- Study completion7 Oct 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pompe-DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre for Analytical Biochemistry and Biomedical Mass Spectrometry
- Sponsor type
- University, hospital or other
- Collaborators
- University of Giessen
- Responsible party
- Principal investigator, Prof. Dr. Michael Przybylski, Centre for Analytical Biochemistry and Biomedical Mass Spectrometry
- Investigators
- Michael Przybylski, PhD, Principal investigator, Centre for Analytical Biochemistry, 65428 Ruesselsheim am Main, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05448131
- Sponsor's protocol ID
- SGZ-2020-13329
- Status last verified
- Feb 2023
- First submitted
- 29 Jun 2022
- Last updated
- 21 Feb 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Towards an Individually Tailored Enzyme Replacement Therapy in Pompe Disease: A Controlled Study for Elucidation of Molecular Structures Contributing to Enzyme Uptake and Immunoreactivity
- ClinicalTrials.gov ID
- NCT05448131
- Acronym / sponsor ID
- SGZ-2020-13329
- Conditions
- Pompe-Disease
- Keywords
- Antibodies
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Centre for Analytical Biochemistry and Biomedical Mass SpectrometryUniversity, hospital or other
- Collaborators
- University of Giessen
- Study start
- 1 Feb 2023 (actual)
- Primary completion
- 6 Aug 2024 (estimated)
- Study completion
- 7 Oct 2024 (estimated)
- First posted
- 7 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In the first part of this study, the aim is to characterize the molecular structure of wildtype GAA and, in particular, of mutated GAA variants with and without HSAT, in order to learn how mutation impairs uptake of GAA into the cell via the M6P receptor. In the second part of the study the aim is to learn to which epitopes antibodies bind and to which not. To accomplish this the investigators will synthesize and chemically modify the epitope peptides, in order to block effectively antibodies directed against the therapeutic enzyme.
Detailed description
Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA = alglucosidase alfa) is available since 2006, and has been shown effective in IOPD and LOPD; however the treatment response is variable and imperfect. This has prompted the development of a next-generation rhGAA with increased glycosylation and improved muscle cell uptake (avalglucosidase alfa). The efficacy of ERT significantly depends on the glycosylation status of the enzyme determining muscle cell uptake via the mannose-6-phosphate (M6P) receptor, and on the formation of antibodies directed against the recombinant enzyme. The impact of immunological factors on efficacy is highlighted by the occurrence of high sustained antibody titers (HSAT) in IOPD patients producing no GAA at all (CRIM-negative), that result in a worse outcome similar to that of untreated patients, if no immunomodulating medication is given. Such HSAT can also occur in IOPD patients synthesizing a non-functional GAA (CRIM-positive) and in some late onset Pompe Disease (LOPD) patients.
In the first part of this study, the investigators aim to characterize the molecular structure of wildtype GAA and, in particular, of mutated GAA variants with and without HSAT, in order to learn how mutation impairs uptake of GAA into the cell via the M6P receptor. To accomplish this, 5 healthy subjects and 45 Pompe disease patients will be studied (15 IOPD and 30 LOPD). The investigators will identify antibody epitopes in the sera of patients with rhGAA antibodies and determine and compare quantitatively their binding affinities, by using a combination of proteolytic affinity-mass spectrometry and surface plasmon resonance biosensor analysis. The investigators reason that specific mutations may affect the epitope status differently. Related to this, the investigators also speculate that glycosylations and M6P residues could modify epitopes in their close vicinity. These results will help to understand where the antibody binding epitopes are located.
In the second part of the study the investigators aim to learn to which epitopes antibodies bind and to which not. To accomplish this the epitope peptides will be synthesized and chemically modified, in order to block effectively antibodies directed against the therapeutic enzyme. Applying high affinity GAA epitope peptides capable of binding neutralizing antibodies is expected to potentially improve efficacy and safety of ERT, thereby providing a new targeted and personalized immunotolerance approach.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- 50 patients who meet all eligibility criteria will be enrolled in the study.
Key inclusion criteria (5 listed)
- All patients or their legal guardian and healthy volunteers with normal GAA enzyme activity and genotype will give informed consent to participate in this explorative, cross-sectional study.
- IOPD/LOPD patients will have a confirmed diagnosis of Pompe disease based on enzyme activity reduction and genetic GAA mutations.
- Both CRIM-positive and CRIM-negative IOPD patients will be included.
- Patients with IOPD/LOPD will be on enzyme replacement therapy on their individual treatment regime.
- Healthy volunteers will be included as controls for wildtype GAA analysis.
Key exclusion criteria (3 listed)
- Patient/healthy volunteer or legal guardian do not agree to give informed consent.
- The patient/healthy volunteer is not capable to adhere to the study protocol.
- The patient is not treated with enzyme replacement therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Determination of epitope numbers of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies
Time frame: Only at baseline visit
Epitope numbers of wtGAA, rhGAA, and mutated GAAs will determine the number of Pompe patients with polyclonal and monoclonal antibodies, and determine whether specific antibodies are more prevalent than others among Pompe patients.
Determination of epitope locations of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies
Time frame: Only at baseline visit
Epitope locations of wtGAA, rhGAA, and mutated GAAs will determine the number of Pompe patients with polyclonal and monoclonal antibodies, and determine whether specific antibody epitopes are more prevalent than others among Pompe patients.
Determination of epitope- specific affinities of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies
Time frame: Only at baseline visit
Epitope- specific affinities of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies in PD patients will be determined for correlation with mutations in GAA structure
2 secondary outcomes
Determination of the number of PD patients with specific neutralizing antibody epitopes
Time frame: Only at baseline visit
Determination of antibody titers in PD patients
Time frame: Only at baseline visit
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Przybylski, PhD principal investigator
Centre for Analytical Biochemistry, 65428 Ruesselsheim am Main, Germany
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pompe-Disease, run by Centre for Analytical Biochemistry and Biomedical Mass Spectrometry at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Michael Przybylski, PhD (+49 6142 8345511, michael.przybylski@stw.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of epitope numbers of acid-alpha-glucosidase (wtGAA; rhGAA; mutated GAA) antibodies (time frame: Only at baseline visit). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2023.