Document


UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K

CURRENT REPORT PURSUANT TO
SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934

Date of Report (Date of earliest event reported): April 30, 2019
http://api.tenkwizard.com/cgi/image?quest=1&rid=23&ipage=12863709&doc=4
AMICUS THERAPEUTICS, INC.
(Exact Name of Registrant as Specified in Its Charter)

Delaware
(State or Other Jurisdiction of
Incorporation)

   001-33497
  71-0869350
 (Commission File Number)
(IRS Employer Identification No.)
 
 
1 Cedar Brook Drive, Cranbury, NJ
08512
  (Address of Principal Executive Offices)    
     (Zip Code)
                  
Registrant’s telephone number, including area code: (609) 662-2000

(Former Name or Former Address, if Changed Since Last Report.)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

o
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

o
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

o
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

o
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company o

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. o






Item 8.01. Other Events

On April 30, 2019, Amicus Therapeutics, Inc. (the "Company") issued a press release announcing initial positive preclinical Pompe disease gene therapy data at the American Society of Gene & Cell Therapy ("ASGCT") 22nd Annual Meeting in Washington D.C. A copy of this press release is attached hereto as Exhibit 99.1. In addition, the Company will be using the presentation attached as Exhibit 99.2 during its conference call and webcast. Both exhibits are incorporated herein by reference.


Item 9.01 Financial Statements and Exhibits
Exhibits:

Exhibit No.
Description








SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.


 
AMICUS THERAPEUTICS, INC.
Date: April 30, 2019
By: /s/ Ellen S. Rosenberg
 
Name: Ellen S. Rosenberg
 
Title: Chief Legal Officer



Exhibit
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Amicus Therapeutics Presents Positive Preclinical Pompe Disease Gene Therapy Data at American Society of Gene & Cell Therapy (ASGCT) 22nd Annual Meeting

Preclinical Studies Show Robust Uptake and Glycogen Reduction in Multiple Tissues, Including Brain and Spinal Cord

Initial Validation for Collaboration Combining Amicus-Engineered Transgenes with Penn’s AAV Gene Therapy Technologies

Significant and Broad New Amicus Platform Technology with Potential to Engineer Lysosomal Proteins to Enhance Targeting

Ongoing Preclinical Studies to Confirm Clinical Candidate Selection in 2019

Conference Call Today at 8:30am

CRANBURY, NJ, April 30, 2019 – Amicus Therapeutics (Nasdaq: FOLD) today announced initial preclinical data from its investigational adeno-associated viral (AAV) gene therapy program for Pompe disease in mice. These data will be highlighted in a poster (Poster 82, Abstract 518) entitled “Development of a Novel Gene Therapy for Pompe Disease: Engineered Acid Alpha-Glucosidase Transgene for Improved Expression and Muscle Targeting,” at the American Society of Gene & Cell Therapy (ASGCT) 22nd Annual Meeting in Washington, D.C. today at 5:00 p.m. ET.

Pompe disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Reduced or absent levels of GAA lead to accumulation of glycogen in cells, which results in the clinical manifestations of Pompe disease. Amicus, in collaboration with the Gene Therapy Program of the Perelman School of Medicine at the University of Pennsylvania (Penn), is developing a novel gene therapy for Pompe disease that combines the Amicus protein-engineering and glycobiology expertise with Penn’s adeno associated virus (AAV) gene transfer technologies.

This initial preclinical study used a single high dose of AAV in GAA knockout mice with either natural unmodified hGAA (“natural hGAA”) or an Amicus/Penn engineered hGAA transgene with a lysosomal-targeting cell receptor binding motif (“engineered hGAA”). The Amicus/Penn engineered hGAA is designed for optimal expression, secretion, and targeting which enables efficient cross-correction in target tissues (via the binding motif).

Preclinical Poster Highlights for Amicus/Penn AAV Gene Therapy for Pompe Disease:
The Amicus/Penn hGAA AAV gene therapy demonstrated more uniform cellular uptake and lysosomal targeting compared to natural hGAA AAV gene therapy.
The engineered hGAA AAV gene therapy demonstrated robust glycogen reduction in all key tissues in Pompe disease that were assessed.
In the central nervous system (CNS), the engineered hGAA AAV gene therapy showed robust glycogen reduction in neuronal cells, suggesting this may be an effective way to address neuronal aspects of Pompe disease. Natural hGAA AAV gene therapy did not show glycogen reduction in neuronal cells.
Initial findings validate the Amicus/Penn collaboration, as well as the potential of this platform to design constructs that enhance protein targeting across multiple lysosomal disorders.
Additional preclinical studies to evaluate this engineered hGAA with various doses and routes of AAV administration are underway.
The Pompe AAV gene therapy program builds upon the protein engineering and manufacturing expertise used to successfully develop AT-GAA, the Company’s late-stage enzyme replacement therapy (ERT)-chaperone treatment paradigm.




Hung Do, PhD, Chief Science Officer of Amicus Therapeutics, stated, “These very important preclinical results validate our capabilities to develop engineered GAA proteins that can efficiently cross-correct target cells and tissues via a gene replacement therapy for Pompe disease. This approach may be applicable to other lysosomal disorders as we continue to combine our Amicus protein engineering expertise, together with Penn’s vector engineering expertise, to develop novel gene therapies.”

John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, added, “Developing a potential cure for Pompe has been a personal and professional goal for many years. These data are profound and it is extremely rewarding to see these preclinical results that show our Amicus engineered GAA is optimized for uptake into target tissues and gets to the right cellular compartments, especially in the central nervous system. These data also provide preliminary and compelling evidence that the Amicus technology to design constructs that enhance protein targeting may be a significant platform for multiple lysosomal disorders. As these data exceed our expectations, our preclinical studies are progressing well ahead of schedule and we now expect to select a clinical candidate in 2019 to move forward into IND-enabling studies. Our mission has always been to develop potential best in class medicines and that is precisely what we are doing with both our novel, late-stage treatment paradigm AT-GAA as well as this preclinical gene therapy program.”

Amicus is currently developing AAV gene therapies in collaboration with the Gene Therapy Program of the Perelman School of Medicine at the University of Pennsylvania (Penn) for Pompe disease, Fabry disease, CDKL5 deficiency disorder (CDD) and one additional undisclosed rare metabolic disease. The agreement between Amicus and Penn is a Research, Collaboration and License Agreement, providing funding to Penn to advance the preclinical research programs in the Wilson Lab and to license certain technologies invented under the funded Research Collaboration.

“Amicus has differentiated itself by focusing on proteins and protein engineering, with a specific track record in the lysosomal disorders, which I believe are critically important to developing AAV gene therapies that can safely and effectively address these diseases,” said James M. Wilson, MD PhD, Professor of Medicine and Pediatrics at the Perelman School of Medicine at Penn. “These initial preclinical results are a significant step in highlighting our collaboration to rapidly advance gene therapies into the clinic for patients with urgent unmet needs in a disease like Pompe. These results demonstrate that the Amicus gene therapy that we have jointly developed has the potential to address both the neuromuscular as well as the motor neuron aspects of Pompe disease.”

Conference Call and Webcast on April 30, 2019 at 8:30 a.m. ET
Amicus Therapeutics will host a conference call and audio webcast today, April 30, 2019 at 8:30 a.m. ET to discuss the preclinical data presented at ASGCT. Interested participants and investors may access the conference call by dialing 877-303-5859 (U.S./Canada) or 678-224-7784 (international), conference ID: 1866796.

A live audio webcast and accompanying slide deck can also be accessed via the Investors section of the Amicus Therapeutics corporate website at http://ir.amicusrx.com/, and will be archived for 30 days. Web participants are encouraged to register on the website 15 minutes prior to the start of the call. A replay of the call will be available for seven days beginning at 11:30 a.m. ET on April 30, 2019. Access numbers for this replay are 855-859-2056 (U.S./Canada) and 404-537-3406 (international); conference ID: 1866796.

About Pompe Disease
Pompe disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Reduced or absent levels of GAA leads to accumulation of glycogen in cells, which results in the clinical manifestations of Pompe disease. The disease can be debilitating, and is characterized by severe muscle weakness that worsens over time. Pompe disease ranges from a rapidly fatal infantile form with significant impacts to heart function to a more slowly progressive, late-onset form primarily affecting skeletal muscle. It is estimated that Pompe disease affects approximately 5,000 to 10,000 people worldwide.


About Amicus Therapeutics
Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the company’s website at www.amicusrx.com, and follow us on Twitter and LinkedIn.


Forward-Looking Statements



This press release contains "forward- looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to initial preclinical data from its investigational adeno-associated viral (AAV) gene therapy program for Pompe disease in mice and the potential implications of these data for the future advancement and development of a gene therapy for Pompe disease and other lysosomal disorders and development of potential platform technologies. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” "confidence," "encouraged," “potential,” “plan,” “targets,” “likely,” “may,” “will,” “would,” “should” and “could,” and similar expressions or words identify forward-looking statements. The forward looking statements included in this press release are based on management's current expectations and belief's which are subject to a number of risks, uncertainties and factors, including that the preliminary data based on a small patient sample and reported before completion of the study will not be predictive of future results, that results of additional preliminary data or data from the completed study or any future study will not yield results that are consistent with the preliminary data presented, that the Company will be not able to demonstrate the safety and efficacy of AT-GAA, that later study results will not support further development, or even if such later results are favorable, that the Company will not be able to successfully complete the development of, obtain regulatory approval for, or successfully commercialize AT-GAA. In addition, all forward looking statements are subject to the other risks and uncertainties detailed in our Annual Report on Form 10-K for the year ended December 31, 2018. As a consequence, actual results may differ materially from those set forth in this press release. You are cautioned not to place undue reliance on these forward looking statements, which speak only of the date hereof. All forward looking statements are qualified in their entirety by this cautionary statement and we undertake no obligation to revise this press release to reflect events or circumstances after the date hereof.
        
CONTACTS:

Investors/Media:
Amicus Therapeutics
Sara Pellegrino, IRC
Vice President, Investor Relations & Corporate Communications
spellegrino@amicusrx.com

(609) 662-5044

Media:

Amicus Therapeutics
Marco Winkler
Director, Corporate Communications

mwinkler@amicusrx.com
(609) 662-2798



FOLD–G


exhibit992
Preclinical Pompe Gene Therapy Results at ASGCT Conference Call & Webcast April 30, 2019


 
2 Forward-Looking Statements This presentation contains "forward- looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to initial preclinical data from its investigational adeno-associated viral (AAV) gene therapy program for Pompe disease in mice and the potential implications of these data for the future advancement and development of a gene therapy for Pompe disease and other lysosomal disorders and development of potential platform technologies. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” "confidence," "encouraged," “potential,” “plan,” “targets,” “likely,” “may,” “will,” “would,” “should” and “could,” and similar expressions or words identify forward-looking statements. The forward looking statements included in this press release are based on management's current expectations and belief's which are subject to a number of risks, uncertainties and factors, including that the preliminary data based on a small patient sample and reported before completion of the study will not be predictive of future results, that results of additional preliminary data or data from the completed study or any future study will not yield results that are consistent with the preliminary data presented, that the Company will be not able to demonstrate the safety and efficacy of AT-GAA, that later study results will not support further development, or even if such later results are favorable, that the Company will not be able to successfully complete the development of, obtain regulatory approval for, or successfully commercialize AT-GAA. In addition, all forward looking statements are subject to the other risks and uncertainties detailed in our Annual Report on Form 10-K for the year ended December 31, 2018. As a consequence, actual results may differ materially from those set forth in this press release. You are cautioned not to place undue reliance on these forward looking statements, which speak only of the date hereof.


 
Pompe Disease 3 Pompe Disease Overview Pompe Disease is a Fatal Neuromuscular and Motorneuron Disorder that Affects a Broad Range of People 5,000 – 10,000+ patients Respiratory and cardiac Age of onset ranges from infancy to diagnosed WW1; newborn failure are leading causes of morbidity adulthood screening suggests underdiagnosis and mortality Deficiency of GAA leading to glycogen Symptoms include muscle weakness, ~$900M+ Global Pompe accumulation and cellular dysfunction respiratory failure, and cardiomyopathy ERT sales in FY182 1. National Institute of Neurological Disorders and Stroke (NIH). 2. Sanofi Press Release & 10-K


 
Amicus Gene Therapy Programs 4 Amicus Protein Engineering Expertise & Technologies for Gene Therapy Collaboration to Enable Greater Protein Expression and Delivery at Lower Gene Therapy Doses Increased Increased Improved Protein Protein Protein Targeting & Expression Secretion Stabilization Novel untranslated sequences Effective signal sequences to Targeting moieties to avoid inhibition of increase protein expression & initiation and drive efficient secretion Protein design protein synthesis


 
Development of a Novel Gene Therapy for Pompe Disease: Engineered Acid Alpha- Glucosidase Transgene for Improved Expression and Muscle Targeting American Society of Gene & Cell Therapy (ASGCT) 22nd Annual Meeting April 30, 2019


 
Preclinical Pompe Gene Therapy Results at ASGCT 6 AAV Gene Therapy Initial High-Dose Preclinical POC Study • AAV Transgene: AAV Expressing Trans-Gene Co nstructs – Natural-hGAA (AAV.hGAA nat) – Engineered-hGAA (AAV.hGAA eng) Native Signal Peptide Natural hGAA • Dose\Route: – 5e11 gc/mouse (~2.5e13 gc/kg) Kozak GAA – Tail Vein IV Sequence More Efficient • Animal Model: Signal – Pompe Model Gaa -/- B6:129-GAAtm1Rabn/J (aka 6neo) Peptide Engineered hGAA – Wild-type Gaa +/+ (Pompe model litter-mates) Kozak GAA + lysosomal targeting motif • Gender: Sequence – Male – Female Study Design: 4 Week Animal Study • Age: 4-6 weeks at AAV dosing 5e11 gc/mouse ~2.5e13 gc/kg Week 1 Week 2 Week 3 Week 4 7d Day 21 Day 28 Serum Serum Plasma Tissue


 
Preclinical Pompe Gene Therapy Results at ASGCT 7 GAA Plasma Activity, Concentration and Cell-Surface Receptor Binding Binding to Intended Receptor Day 28 Plasma Samples used to evaluate receptor binding • Engineered hGAA was able to efficiently bind the • High levels of engineered and natural hGAA were intended receptor to enable cellular uptake measured in plasma at day 28


 
Preclinical Pompe Gene Therapy Results at ASGCT 8 Tibialis Anterior – 28 days after AAV Gene Therapy Engineered hGAA was more Efficient at Cross-Correction as Indicated by Greater Cellular Uptake, Uniform Glycogen Reduction and Cell Pathology Correction Glycogen PAS - Tibialis anterior Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type • GAA activity in the tibialis anterior was ~15 – 20 fold higher than wild-type levels for both engineered hGAA and natural hGAA 20x • PAS staining showed more uniform and complete glycogen reduction and clearance of autophagic vacuoles for engineered hGAA 60x • PAS staining showed incomplete glycogen Gaa -/- Gaa -/- Gaa -/- Gaa +/+ reduction and less clearance of autophagic hGAA IHC - Tibialis anterior vacuoles for natural hGAA (white arrows) Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type • IHC illustrated greater cellular uptake (black arrows) of engineered hGAA compared to natural 20x hGAA • Similar results seen in other muscle groups (see 60x Appendix) Gaa -/- Gaa -/- Gaa -/- Gaa +/+ Periodic acid–Schiff (PAS) is a staining method used to detect polysaccharides such as glycogen in tissues


 
Preclinical Pompe Gene Therapy Results at ASGCT 9 Brain– 28 days after AAV Gene Therapy Engineered hGAA was able to Cross-Correct the Brain at Low Levels Due to Efficient Cellular Uptake while Natural hGAA was not able to Cross-Correct at Similar Expression Levels Glycogen Luxol/PAS - Brain Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type • GAA activity in the brain was ~5-fold lower than wild-type levels for both engineered 1x hGAA and natural hGAA • Both engineered hGAA and natural hGAA 20x likely produced by the choroid plexus and secreted into the cerebrospinal fluid Gaa -/- Gaa -/- Gaa -/- Gaa +/+ hGAA IHC - brainstem and choroid plexus • Glycogen close to wild-type levels for Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type engineered hGAA, even though activity was only 20% of wild-type levels 20x • Little/no glycogen clearance with natural hGAA 20x Gaa -/- Gaa -/- Gaa -/- Gaa +/+


 
Preclinical Pompe Gene Therapy Results at ASGCT 10 Spinal Cord– 28 days after AAV Gene Therapy Engineered hGAA was able to Reduce Glycogen Efficiently in the Spinal Cord while Little GGlycogenlycogen Luxo lReduction/PAS – Spinal Cwasord Observed for Natural Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type hGAA Glycogen Luxol/PAS – Spinal Cord 20x Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type • PAS staining showed that glycogen levels Gaa -/- Gaa -/- Gaa -/- Gaa +/+ were close to wild-type in ventral horn, 20x including motor neurons, for engineered Gaa -/- Gaa -/- Gaa -/- Gaa +/+ hGAA hGAA IHC – Spinal Cord • PAS staining showed that glycogen levels Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type were closer to vehicle in ventral horn, including motor neurons, for natural hGAA IHC – Spinal Cord hGAA (white arrows) Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type 20x • IHC demonstrated a stronger signal in motor neurons from animals receiving engineered hGAA compared with natural 20x hGAA (black arrows) 60x Gaa -/- Gaa -/- Gaa -/- Gaa +/+ 60x Gaa -/- Gaa -/- Gaa -/- Gaa +/+


 
Preclinical Pompe Gene Therapy Results at ASGCT 11 Conclusions • AAV gene therapy expressing the engineered hGAA led to more uniform cellular uptake, glycogen reduction, and resolved cellular dysfunction via efficient cross-correction. • AAV gene therapy expressing the engineered hGAA demonstrated efficient cross-correction with resolution of cellular pathology in the CNS at low expression levels. At similar expression levels, natural hGAA did not demonstrate such effects.


 
Preclinical Pompe Gene Therapy Results at ASGCT 12 Program Status and Anticipated Milestones Initial Findings Validate Amicus/Penn Collaboration Combining Amicus-Engineered Transgenes with Penn’s AAV Gene Therapy Technologies • Pompe AAV gene therapy program builds upon protein engineering and manufacturing expertise used to successfully develop AT-GAA • Additional preclinical studies underway (various doses and routes of AAV administration) • Selection of clinical candidate in 2019 to move into IND-enabling studies • Platform potential to design constructs that enhance protein targeting across multiple lysosomal disorders


 
Thank You “Our passion for making a difference unites us” -Amicus Belief Statement


 
Appendix


 
Preclinical Pompe Gene Therapy Results at ASGCT 15 Quadriceps – 28 days after AAV Gene Therapy Engineered hGAA was more efficient at cross-correction, indicated by greater cellular uptake, lysosomal targeting, and uniform glycogen reduction. Glycogen PAS - Quadriceps Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type • GAA activity in the quadriceps was ~20 fold higher 20x than wild-type levels for both engineered hGAA and natural hGAA • Glycogen reduction was more uniform for engineered 60x hGAA by PAS staining Gaa -/- Gaa -/- Gaa -/- Gaa +/+ • IHC illustrated greater cellular uptake (solid arrows) of engineered hGAA compared to natural hGAA hGAA IHC - Quadriceps Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type 20x 60x Gaa -/- Gaa -/- Gaa -/- Gaa +/+ Periodic acid–Schiff (PAS) is a staining method used to detect polysaccharides such as glycogen in tissues


 
Preclinical Pompe Gene Therapy Results at ASGCT 16 Triceps – 28 days after AAV Gene Therapy Engineered hGAA was more efficient at cross-correction, indicated by greater cellular uptake, lysosomal targeting, and uniform glycogen reduction. Glycogen PAS - Triceps Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type • GAA activity in the triceps was ~10 – 15 fold higher than wild-type levels for both engineered hGAA and 20x natural hGAA • PAS staining showed more complete and uniform glycogen reduction and clearance of autophagic 60x vacuoles for engineered hGAA Gaa -/- Gaa -/- Gaa -/- Gaa +/+ • PAS staining showed incomplete glycogen reduction hGAA IHC - Triceps and less clearance of autophagic vacuoles for natural Vehicle AAV.hGAA nat AAV.hGAA eng Wild-Type hGAA (open arrows) • IHC illustrated greater cellular uptake (solid arrows) of 20x engineered hGAA compared to natural hGAA 60x Gaa -/- Gaa -/- Gaa -/- Gaa +/+ Periodic acid–Schiff (PAS) is a staining method used to detect polysaccharides such as glycogen in tissues


 
Preclinical Pompe Gene Therapy Results at ASGCT 17 Early Proof of Principle for Optimized Gene Therapy Amicus DNA Constructs Enable Optimized Gene Therapy in Pompe and Fabry GAA Binding to Intended Receptor SecretedS e c re te d GAArh G A Ain i nMedia M e d ia 8 0 0 0 y t 8 0 A m ic u s G T - G A A i ) v i ) r y t r W T r h G A A t u i c h 6 0 0 0 o / v 6 0 A i h L t / c A L m / A A l 4 0 0 0 Pompe m 4 0 / o G l A o m A d n n m G ( 2 0 0 0 A m ic u s G T - G A A u 2 0 n ( o W T r h G A A B 0 0 0 2 4 6 0 2 0 4 0 6 0 8 0 1 0 0 D a y s rh G A A (n M ) Alpha-Gal Activity: pH 7.4 Alpha-Gal Activity: pH 4.6 W T ) p H 4 .6 3 0 0 ) c o n s tru c t 1 % W T ( p H 7 .4 % c o n s tru c t 2 ( y c o n s tru c t 1 3 0 0 t 2 5 0 i y v t i c o n s tru c t 2 i 2 5 0 t 2 0 0 v c i t A 2 0 0 c Fabry 1 5 0 l A a l 1 5 0 u 1 0 0 a d i u 1 0 0 s d 5 0 i e s R 5 0 0 e 0 1 2 3 4 5 6 7 R 0 T im e (d a y s )