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Define biotechnology as well as recombinant proteins and how they are produced
Describe the 2 different forms of agalsidase: agalsidase-α and agalsidase-β
Discuss agalsidase-β dose messaging, including the results from various publications
Note: Bolded items will be defined in the glossary
After completing this training, learners will be able to:
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LESSON 1 OF 8
Learning Objectives
LESSON 2 OF 8
Rationale for This Training
Download the video of the "Save the Date: GEM Fabry Medical Workshop" by selecting the link below.
Refer to footnotes for timestamps.
Description of course and why it’s important
What is Biotechnology?
LESSON 3 OF 8
Overview of Biotechnology
Recombinant Proteins and How They are Designed
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Recombinant proteins are foreign proteins produced by host cells that wouldn’t normally produce that foreign protein
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DNA inserted into a bacterial cell culture will amplify
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Utilization of bioreactors in strict optimized protein production
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Upstream process and downstream processes
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Human proteins of interest are produced by host bacteria
Biotechnology is a field of medicine that uses technology to produce and modify products such as proteins.
LESSON 4 OF 8
Forms of Agalsidase
There are 2 enzyme replacement therapy products available for the treatment of Fabry disease. They have different dosing regimens.
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1.0 mg/kg EOW by IV Infusion at a rate no greater than 15 mg/hour during the first infusion
0.2 mg/kg EOW by IV infusion over 40 minutes
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Both share the same amino acid sequence, but do vary slightly
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Isoforms are common in products produced by recombinant DNA technology
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Chromatography shows that the 2 different forms are non-identical molecules
Glycosylation
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Plays a key role in producing sialic acid
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N-glycolylneuraminic acid is a sialic acid found in animals but not humans as we cannot synthesize it
Due to the difference in molecular structure, there may be differences in
their immunogenicity profiles, including the formation of anti-drug antibodies
ANIMAL
Agalsidase-β
HUMAN
Agalsidase-α
Timestamps: 0:16:09; 0:16:20; 0:30:59; 0:30:59; 0:20:01; 0:20:36; 0:20:43; 0:24:56; 0:28:29; 0:29:15; 0:29:16; 0:18:13
Agalsidase-α and agalsidase-β are produced in different cell lines.
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Production of the Two Different Forms of Agalsidase
LESSON 5 OF 8
Gb3 Podocyte Clearance
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Four publications were covered on the topic of Gb3 podocyte clearance and renal pathology19
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Tondel et al. 2013, Skrunes et al. 2017, Skrunes et al. 2017, Najafian et al. 2016
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Timestamps: 0:06:44; 0:10:05; 0:13:07; 0:13:45; 0:14:17; 0:14:50
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Some of these studies show a dose-response relationship for podocyte clearance
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Not all studies show complete clearance of Gb3 from podocytes with agalsidase-β
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Podocyte Gb3 clearance is seen with both agalsidase-β and agalsidase-α in some of these studies
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No difference is seen between ERTs in Gb3 clearance from other renal cell types
Summary
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Podocytes are not the only cell type that play a role in renal pathology in Fabry disease
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No correlations or conclusions can be made regarding clinical outcomes
Switching From Agalsidase-β to Agalsidase-α
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Six publications were covered on the topic of switching treatment from agalsidase-β to agalsidase-α22
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Weidmann et al. 2014, Lenders et al. 2016, Kramer et al. 2018, Lenders et al. 2021, Pisani et al. 2017, Goker-Alpan et al. 2015
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There was no difference seen in clinical events between patients who switched from agalsidase-β to agalsidase-α or those who continued treatment with agalsidase-β
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In some of the studies, a pronounced reduction in eGFR was observed in patients who switched from agalsidase-β to agalsidase-α, but others showed a stable disease course after the switch
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In the largest cohort of patients who switched from agalsidase-β to agalsidase-α based on an FDA approved protocol, and clinical and biochemical parameters remained stable for at least 2 years after the switch
Pooled Analyses and Meta-analyses
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El Dib et al. 201624
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There was no evidence to support if alfa or beta form is superior
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Adverse events were more significant in the beta group as compared to placebo
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El Dib et al. 201725
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Beta is associated with a significantly lower incidence of renal, cardiovascular, and cerebrovascular events compared to no ERT
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Authors imply that beta should be recommended over alfa
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Timestamps: 0:45:04; 0:52:33; 0:53:20; 0:54:26
Head-to-head and Comparator Studies
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Significant head-to-head study comparing agalsidase-β and agalsidase-α at the approved doses
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Sirrs S et al.26
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Primary endpoint was the composite clinical endpoint of renal, cardiovascular, and cerebrovascular events, and death
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There was no difference between the groups (agalsidase-β vs. agalsidase-α) in the primary endpoint at 5 years and 8 years
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There was no difference in efficacy outcomes between agalsidase-α 0.2 mg/kg EOW and the approved dose of agalsidase-β 1.0 mg/kg EOW
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There have been many comparator studies, but one discusses antibodiesArends et al. 201827
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Significantly more patients treated with agalsidase-β developed antibodies compared with patients receiving agalsidase-α
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There was a higher prevalence of neutralizing antibodies in patients treated with agalsidase-β
Timestamps: 0:57:40; 0:59:38
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Bulleted summary of key concepts of course
LESSON 6 OF 8
Summary
LESSON 7 OF 8
Glossary
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