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LQGAQMGQPW CFFPPSYPSY KLENLSSSEM GYTATLTRTT PTFFPKDILT LRLDVMMETE
NRLHFTIKDP ANRRYEVPLE TPRVHSRAPS PLYSVEFSEE PFGVIVHRQL DGRVLLNTTV
APLFFADQFL QLSTSLPSQY ITGLAEHLSP LMLSTSWTRI TLWNRDLAPT PGANLYGSHP
FYLALEDGGS AHGVFLLNSN AMDVVLQPSP ALSWRSTGGI LDVYIFLGPE PKSVVQQYLD
VVGYPFMPPY WGLGFHLCRW GYSSTAITRQ VVENMTRAHF PLDVQWNDLD YMDSRRDFTF
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ELENPPYVPG VVGGTLQAAT ICASSHQFLS THYNLHNLYG LTEAIASHRA LVKARGTRPF
VISRSTFAGH GRYAGHWTGD VWSSWEQLAS SVPEILQFNL LGVPLVGADV CGFLGNTSEE
LCVRWTQLGA FYPFMRNHNS LLSLPQEPYS FSEPAQQAMR KALTLRYALL PHLYTLFHQA
HVAGETVARP LFLEFPKDSS TWTVDHQLLW GEALLITPVL QAGKAEVTGY FPLGTWYDLQ
TVPIEALGSL PPPPAAPREP AIHSEGQWVT LPAPLDTINV HLRAGYIIPL QGPGLTTTES
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Avalglucosidase alfa (USAN/INN);
Avalglucosidase alfa (genetical recombination) (JAN);
To treat late-onset Pompe disease
FDA APPROVED Nexviazyme, 2021/8/6, Enzyme replacement therapy product
Treatment of Pompe disease
Biologic License Application (BLA): 761194
Company: GENZYME CORP
https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pompe-diseaseFor Immediate Release:August 06, 2021
Today, the U.S. Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease.
Patients with Pompe disease have an enzyme deficiency that leads to the accumulation of a complex sugar, called glycogen, in skeletal and heart muscles, which cause muscle weakness and premature death from respiratory or heart failure. Normally, glycogen—the stored form of glucose—breaks down to release glucose into the bloodstream to be used as fuel for the cells.
“Pompe disease is a rare genetic disease that causes premature death and has a debilitating effect on people’s lives,” said Janet Maynard, M.D., deputy director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine in the FDA’s Center for Drug Evaluation and Research. “Today’s approval brings patients with Pompe disease another enzyme replacement therapy option for this rare disease. The FDA will continue to work with stakeholders to advance the development of additional new, effective and safe therapies for rare diseases, including Pompe disease.”
Nexviazyme, an enzyme replacement therapy, is an intravenous medication that helps reduce glycogen accumulation. The effectiveness of Nexviazyme for the treatment of Pompe disease was demonstrated in a study of 100 patients who were randomized to take Nexviazyme or another FDA-approved enzyme replacement therapy for Pompe disease. Treatment with Nexviazyme improved lung function similar to the improvement seen with the other therapy.
The most common side effects included headache, fatigue, diarrhea, nausea, joint pain (arthralgia), dizziness, muscle pain (myalgia), itching (pruritus), vomiting, difficulty breathing (dyspnea), skin redness (erythema), feeling of “pins and needles” (paresthesia) and skin welts (urticaria). Serious reactions included hypersensitivity reactions like anaphylaxis and infusion-associated reactions, including respiratory distress, chills and raised body temperature (pyrexia). Patients susceptible to fluid volume overload or with compromised cardiac or respiratory function may be at risk for serious acute cardiorespiratory failure.
The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Nexviazyme also received an orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Nexviazyme to Genzyme Corporation.
NEW DRUG APPROVALS
FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease
- The FDA decision date for avalglucosidase alfa, an investigational enzyme replacement therapy, is set for May 18, 2021
- Regulatory submission based on positive data from two trials in patients with late-onset and infantile-onset Pompe disease, respectively
- Avalglucosidase alfa received FDA Breakthrough Therapy and Fast Track designations for the treatment of people with Pompe Disease
- Pompe disease, a rare degenerative muscle disorder, affects approximately 3,500 people in the U.S.
- Milestone reinforces 20+year commitment to Pompe disease community
PARIS – November 18, 2020 – The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application (BLA) for avalglucosidase alfa for long-term enzyme replacement therapy for the treatment of patients with Pompe disease (acid α-glucosidase deficiency). The target action date for the FDA decision is May 18, 2021.
Avalglucosidase alfa is an investigational enzyme replacement therapy designed to improve the delivery of acid alpha-glucosidase (GAA) enzyme to muscle cells, and if approved, would offer a potential new standard of care for patients with Pompe disease.
In October, the European Medicines Agency accepted for review the Marketing Authorization Application for avalglucosidase alfa for long-term enzyme replacement therapy for the treatment of patients with Pompe disease. The Medicines and Healthcare Products Regulatory Agency in the UK has granted Promising Innovative Medicine designation for avalglucosidase alfa.
“The hallmarks of Pompe disease are the relentless and debilitating deterioration of the muscles, which causes decreased respiratory function and mobility,” said Karin Knobe, Head of Development for Rare Diseases and Rare Blood Disorders at Sanofi. “Avalglucosidase alfa is specifically designed to deliver more GAA enzyme into the lysosomes of the muscle cells. We have been greatly encouraged by positive clinical trial results in patients with late-onset and infantile-onset Pompe disease.”
Pompe disease is a rare, degenerative muscle disorder that can impact an individual’s ability to move and breathe. It affects an estimated 3,500 people in the U.S. and can manifest at any age from infancy to late adulthood.i
The BLA is based on positive data from two trials:
- Pivotal Phase 3, double-blind, global comparator-controlled trial (COMET), which evaluated the safety and efficacy of avalglucosidase alfa compared to alglucosidase alfa (standard of care) in patients with late-onset Pompe disease. Results from this trial were presented during a Sanofi-hosted virtual scientific session in June 2020 and in October 2020 at World Muscle Society and the American Association of Neuromuscular and Electrodiagnostic Medicine.
- The Phase 2 (mini-COMET) trial evaluated the safety and exploratory efficacy of avalglucosidase alfa in patients with infantile-onset Pompe disease previously treated with alglucosidase alfa. Results from this trial were presented at the WORLDSymposium, in February 2020.
Delivery of GAA to Clear Glycogen
Pompe disease is caused by a genetic deficiency or dysfunction of the lysosomal enzyme GAA, which results in build-up of complex sugars (glycogen) in muscle cells throughout the body. The accumulation of glycogen leads to irreversible damage to the muscles, including respiratory muscles and the diaphragm muscle supporting lung function, and other skeletal muscles that affect mobility.
To reduce the glycogen accumulation caused by Pompe disease, the GAA enzyme must be delivered into the lysosomes within muscle cells. Research led by Sanofi has focused on ways to enhance the delivery of GAA into the lysosomes of muscle cells by targeting the mannose-6-phosphate (M6P) receptor that plays a key role in the transport of GAA.
Avalglucosidase alfa is designed with approximately 15-fold increase in M6P content, compared to standard of care alglucosidase alfa, and aims to help improve cellular enzyme uptake and enhance glycogen clearance in target tissues.ii The clinical relevance of this difference has not been confirmed.
Avalglucosidase alfa is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority worldwide.
Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.
With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.
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/////////Avalglucosidase alfa, FDA 2021, Nexviazyme, APPROVALS 2021, PEPTIDE, Enzyme replacement therapy , Pompe disease, アバルグルコシダーゼアルファ (遺伝子組換え), Fast Track, Priority Review, Breakthrough Therapy, orphan drug designation, genzyme, sanofi
FDA expands approval of drug to treat Pompe disease to patients of all ages; removes risk mitigation strategy requirements
Human glucosidase, prepro-α-[199-arginine,223-histidine] 
August 1, 2014
The U.S. Food and Drug Administration today announced the approval of Lumizyme (alglucosidase alfa) for treatment of patients with infantile-onset Pompe disease, including patients who are less than 8 years of age. In addition, the Risk Evaluation and Mitigation Strategy (REMS) known as the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program is being eliminated.
Pompe disease is a rare genetic disorder and occurs in an estimated 1 in every 40,000 to 300,000 births. Its primary symptom is heart and skeletal muscle weakness, progressing to respiratory weakness and death from respiratory failure.
The disease causes gene mutations to prevent the body from making enough of the functional form of an enzyme called acid alpha-glucosidase (GAA). This enzyme is necessary for proper muscle functioning. GAA is used by the heart and muscle cells to convert a form of sugar called glycogen into energy. Without the enzyme action, glycogen builds up in the cells and, ultimately, weakens the heart and muscles. Lumizyme is believed to work by replacing the deficient GAA, thereby reducing the accumulated glycogen in heart and skeletal muscle cells.
Lumizyme, a lysosomal glycogen-specific enzyme, was approved by the FDA in 2010 with a REMS to restrict its use to treatment of patients with late (non-infantile) onset Pompe disease who are 8 years of age and older. The REMS was required to mitigate the potential risk of rapid disease progression in the infantile-onset Pompe disease patients and patients with late onset disease less than 8 years of age, and to communicate the risks of anaphylaxis, severe allergic reactions and severe skin and systemic immune mediated reactions to prescribers and patients.
At the time of Lumizyme’s approval, there were insufficient data to support the safety and efficacy of Lumizyme in the infantile-onset Pompe population, so Lumizyme was approved for use only in late onset Pompe disease patients who are at least 8 years of age. Pompe patients with infantile-onset disease and patients younger than 8 years of age continued treatment with Myozyme, which was already approved. Myozyme and Lumizyme, both manufactured by Genzyme Corporation, are produced from the same cell line at different production scales.
This approval provides access to Lumizyme for all Pompe disease patients, regardless of their age.
The FDA reviewed newly available information and determined that Lumizyme and Myozyme are chemically and biochemically comparable. Consequently, the safety and effectiveness of Lumizyme and Myozyme are expected to be comparable. In addition, a single-center clinical study of 18 infantile-onset Pompe disease patients, aged 0.2 to 5.8 months at the time of first infusion, provides further support that infantile-onset patients treated with Lumizyme will have a similar improvement in ventilator-free survival as those treated with Myozyme.
Because data were submitted supporting approval of Lumizyme for all Pompe patients, a REMS restricting its use to a specific age group is no longer necessary. While the risk of anaphylaxis, severe allergic reactions, and severe cutaneous and immune mediated reactions for Lumizyme still exist, these risks are comparable to Myozyme and are communicated in labeling through the Warnings and Precautions, and a Boxed Warning.
“REMS continue to be vital tools for the agency to employ as we work with companies to address the serious risks associated with drugs and monitor their appropriate and safe use in various health care settings,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “The agency remains committed to exercising a flexible and responsible regulatory approach that ensures REMS programs are being effectively and efficiently used and not resulting in an unnecessary burden on health care professionals and patients.”
Health care professionals and patients should also be aware:
- The Warnings and Precautions section of the Lumizyme product label and the Clinical Studies section of the Lumizyme label have been updated to include the safety information of the drug in infantile-onset Pompe disease patients. This includes information from the currently approved Myozyme label and information from a new, uncontrolled study in which patients with infantile onset disease were treated with Lumizyme.
- Lumizyme is approved with a Boxed Warning because of the risk of anaphylaxis, severe allergic reactions, immune-mediated reactions and cardiorespiratory failure.
- Health care professionals should continue to refer to the drug prescribing information for the latest recommendations on prescribing Lumizyme and report adverse events to the FDA’s MedWatch program (http://www.fda.gov/Safety/MedWatch/default.htm).
- Distribution of Lumizyme will no longer be restricted. Health care professionals, healthcare facilities, and patients will no longer be required to enroll in the Lumizyme REMS program (Lumizyme ACE Program) to be able to prescribe, dispense, or receive Lumizyme.
The most commonly reported side effects for Lumizyme were infusion-related reactions and included severe allergic reactions, hives, diarrhea, vomiting, shortness of breath, itchy skin, skin rash, neck pain, partial hearing loss, flushing, pain in extremities, and chest discomfort.
Myozyme and Lumizyme are marketed by Cambridge, Massachusetts-based Genzyme.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
|Country||Patent Number||Approved||Expires (estimated)|
>Alglucosidase alfa AHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGQPWCFF PPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPANR RYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVLLNTTVAPLFFADQFLQLS TSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGGSAHG VFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYWGL GFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAMVQ ELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGSTAFPD FTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPYVPGVVG GTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPFVISRSTFAGHGRY AGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQLGAFYP FMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPLFL EFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPVEALGSLPPP PAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVALTK GGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGV ATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC
|Systematic (IUPAC) name|
|Human glucosidase, prepro-α-[199-arginine,223-histidine] |
|Legal status||FDA approved for children|
|Mol. mass||105338 |
Alglucosidase alfa (Lumizyme, Myozyme, Genzyme) is an enzyme replacement therapy (ERT) orphan drug for treatment of Pompe disease (Glycogen storage disease type II), a rare lysosomal storage disorder (LSD). Chemically speaking, the drug is ananalog of the enzyme that is deficient in patients affected by Pompe disease, alpha-glucosidase. It is the first drug available to treat this disease.
Orphan drug pharmaceutical company, Genzyme, markets alglucosidase alfa as “Myozyme”. In 2006, the U.S. Food and Drug Administration (FDA) approved Myozyme as a suitable ERT treatment for children. Some health plans have refused to subsidize Myozyme for adult patients because it lacks approval for treatment in adults, as well as its high cost (US$300,000/yr for life).
On August 1, 2014 the U.S. Food and Drug Administration announced the approval of Lumizyme (alglucosidase alfa) for treatment of patients with infantile-onset Pompe disease, including patients who are less than 8 years of age. In addition, the Risk Evaluation and Mitigation Strategy (REMS) known as the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program is being eliminated. 
Common observed adverse reactions to alglucosidase alfa treatment are pneumonia, respiratory complications, infections and fever. More serious reactions reported includeheart and lung failure and allergic shock. Myozyme boxes carry warnings regarding the possibility of life-threatening allergic response.
- American Medical Association (USAN). “Alglucosidase alfa” (Microsoft Word). STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. Retrieved 18 December 2007.
- “FDA Approves First Treatment for Pompe Disease” (Press release). FDA. 2006-04-28. Retrieved 2008-07-07.
- Kishnani PS, Corzo D, Nicolino M et al. (2007). “Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease”. Neurology 68 (2): 99–109.doi:10.1212/01.wnl.0000251268.41188.04. PMID 17151339.
- Geeta Anand (2007-09-18). “As Costs Rise, New Medicines Face Pushback”. Wall Street Journal (Dow Jones & Company). Retrieved 2008-07-07.
- cite press release |title=FDA expands approval of drug to treat Pompe disease to patients of all ages; removes risk mitigation strategy requirements |publisher=FDA |date=2014-08-14 |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm407563.htm
- Myozyme (alglucosidase alfa), Genzyme official website
- MTAP (Myozyme Temporary Access Program), Genzyme official website
MYOZYME (alglucosidase alfa), a lysosomal glycogen-specific enzyme, consists of the human enzyme acid α-glucosidase (GAA), encoded by the most predominant of nine observed haplotypes of this gene. MYOZYME is produced by recombinant DNA technology in a Chinese hamster ovary cell line. The MYOZYME manufacturing process differs from that for LUMIZYME®, resulting in differences in some product attributes. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α-1,4- and α-1,6- glycosidic linkages of lysosomal glycogen.
Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 daltons for the polypeptide chain, and a total mass of approximately 110 kilo Daltons, including carbohydrates. Alglucosidase alfa has a specific activity of 3 to 5 U/mg (one unit is defined as that amount of activity that results in the hydrolysis of 1 μmole of synthetic substrate per minute under the specified assay conditions). MYOZYME is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with 10.3 mL
Sterile Water for Injection, USP. Each 50 mg vial contains 52.5 mg alglucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic heptahydrate, 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5.0 mg/mL alglucosidase alfa. MYOZYME does not contain preservatives; each vial is for single use only.