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 * INTRODUCTION

 * OVERVIEW OF BIOTECHNOLOGY

 * CONCLUSION

 * ASSESSMENT QUESTIONS

 * More...


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START COURSE


SINGAPORE FABRY

3



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:

2




1

3

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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.

GEM Fabry Medical Workshop.mp4


Description of course and why it’s important

LESSON 8 OF 8


ASSESSMENT QUESTIONS

START QUIZ




WHAT IS BIOTECHNOLOGY?

LESSON 3 OF 8


OVERVIEW OF BIOTECHNOLOGY

RECOMBINANT PROTEINS AND HOW THEY ARE DESIGNED

 * Recombinant proteins are foreign proteins produced by host cells that
   wouldn’t normally produce that foreign protein

 * DNA inserted into a bacterial cell culture will amplify

 * Utilization of bioreactors in strict optimized protein production
   
   * Upstream process and downstream processes

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



 * Both share the same amino acid sequence, but do vary slightly
   
   * Isoforms are common in products produced by recombinant DNA technology

 * Chromatography shows that the 2 different forms are non-identical molecules


GLYCOSYLATION

 * Plays a key role in producing sialic acid

 * 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

 * Four publications were covered on the topic of Gb3 podocyte clearance and
   renal pathology19
   
   * Tondel et al. 2013, Skrunes et al. 2017, Skrunes et al. 2017, Najafian et
     al. 2016

Timestamps:  0:06:44; 0:10:05; 0:13:07; 0:13:45; 0:14:17; 0:14:50



 * Some of these studies show a dose-response relationship for podocyte
   clearance 

 * Not all studies show complete clearance of Gb3 from podocytes with
   agalsidase-β

 * Podocyte Gb3 clearance is seen with both agalsidase-β and agalsidase-α in
   some of these studies

 * No difference is seen between ERTs in Gb3 clearance from other renal cell
   types


SUMMARY

 * Podocytes are not the only cell type that play a role in renal pathology in
   Fabry disease

 * No correlations or conclusions can be made regarding clinical outcomes




SWITCHING FROM AGALSIDASE-Β TO AGALSIDASE-Α





 * Six publications were covered on the topic of switching treatment from
   agalsidase-β to agalsidase-α22
   
   * 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
      

 * 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
    

 * 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
    

 * 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



 * El Dib et al. 201624
   
   * There was no evidence to support if alfa or beta form is superior
   
   * Adverse events were more significant in the beta group as compared to
     placebo
      

 * El Dib et al. 201725
   
   * Beta is associated with a significantly lower incidence of renal,
     cardiovascular, and cerebrovascular events compared to no ERT
   
   * Authors imply that beta should be recommended over alfa

Timestamps:  0:45:04; 0:52:33; 0:53:20; 0:54:26


HEAD-TO-HEAD AND COMPARATOR STUDIES



 * Significant head-to-head study comparing agalsidase-β and agalsidase-α at the
   approved doses 
   
   * Sirrs S et al.26

 * Primary endpoint was the composite clinical endpoint of renal,
   cardiovascular, and cerebrovascular events, and death

 * There was no difference between the groups (agalsidase-β vs. agalsidase-α) in
   the primary endpoint at 5 years and 8 years

 * 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

 * There have been many comparator studies, but one discusses antibodiesArends
   et al. 201827

 * Significantly more patients treated with agalsidase-β developed antibodies
   compared with patients receiving agalsidase-α

 * There was a higher prevalence of neutralizing antibodies in patients treated
   with agalsidase-β



Timestamps: 0:57:40; 0:59:38

 * Bulleted summary of key concepts of course



LESSON 6 OF 8


SUMMARY

LESSON 7 OF 8


GLOSSARY

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   enim a ante euismod convallis. 
    

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   elementum quam. Praesent vitae felis non arcu efficitur posuere. 
    

 * Lorem ipsum dolor: Sit amet, consectetur adipiscing elit. Vestibulum rutrum
   enim a ante euismod convallis. 
    

 * Nam vulputate: Porta nunc, sit amet tincidunt justo elementum at. Duis ut
   elementum quam. Praesent vitae felis non arcu efficitur posuere. 


 * INTRODUCTION
 * OVERVIEW OF BIOTECHNOLOGY
 * CONCLUSION
 * ASSESSMENT QUESTIONS

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