Cerliponase alfa

Cerliponase alfa
Clinical data
Trade namesBrineura
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intraventricular
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem SID
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC2657H4042N734O793S11
Molar mass59308.57 g·mol−1

Cerliponase alfa, marketed as Brineura, is an enzyme replacement treatment for Batten disease, a neurodegenerative lysosomal storage disease. Specifically, Cerliponase alfa is meant to slow loss of motor function in symptomatic children over three years old with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency, a soluble lysosomal enzyme deficiency.[3] Approved by the United States Food and Drug Administration (FDA) on 27 April 2017, this is the first treatment for a neuronal ceroid lipofuscinosis of its kind, acting to slow disease progression rather than palliatively treat symptoms by giving patients the TPP1 enzyme they are lacking.[4]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[5]

History

TPP1 was identified as the enzyme deficient in CLN2 Batten disease in 1997, via biochemical analysis that identified proteins missing a mannose-6-phosphate lysosomal targeting sequence.[6] A gel electrophoresis was run for known brain proteins with lysosomal targeting sequences to see if a band was missing, indicating a deficiency in that protein. A band appeared to be missing at approximately 46 kDa, confirming its role in CLN2 disease, and almost the entire gene for this unknown protein was sequenced. The gene is located on chromosome 11.[7] Today, it is known that varying mutation types occur in various locations of the gene including the proenzyme region, the mature enzyme region, or the signal sequence regions.[8] After discovery, the recombinant form of TPP1, cerliponase alfa, was first produced in 2000, followed by testing in animal models until 2014.[9] In 2012, BioMarin began the first clinical trial on affected patients using their recombinant DNA technology cerliponase alfa which is synthesized using Chinese hamster ovarian (CHO) cell lines.[3]

Structure of tripeptidyl peptidase 1 (TPP1) enzyme for which cerliponase alfa is a replacement for.

After the success of this clinical trial, the U.S. FDA approved the marketing of cerliponase alfa to patients with CLN2 disease. The approval only applied to patients three years or older as the FDA wants to have more data available on children under the age of three before approving it for younger patients.[4] A ten-year study is being performed[when?] to assess the long term effects of continued use of this drug.[4][10] Cerliponase alfa is developed by BioMarin Pharmaceutical and the drug application was granted both orphan drug designation to provide incentives for rare disease research and the tenth Rare Pediatric Disease Priority Review Voucher.[4] Cerliponase alfa was also approved by European Medicines Agency (EMA) on 30 May 2017.[11] In the United Kingdom NICE evaluated cerliponase alfa for the treatment of CLN2 and deemed it not cost-effective.[12][13] BioMarin announced that the price per infusion is $27,000, coming to $702,000 per year for treatment, though using Medicaid can decrease the cost.[14]

In March 2018, cerliponase alfa was approved in the United States as a treatment for a specific form of Batten disease.[4][15] Cerliponase alfa is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.[4]

The efficacy of cerliponase alfa was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least three years old and had motor or language symptoms.[4] Taking into account age, baseline walking ability and genotype, cerliponase alfa-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.[4]

The safety of cerliponase alfa was evaluated in 24 patients with CLN2 disease aged three to eight years who received at least one dose of cerliponase alfa in clinical studies.[4] The trial was conducted in the United States, United Kingdom, Germany and Italy.[15] The safety and effectiveness of cerliponase alfa has not been established in patients less than three years of age.[4]

Brineura-treated patients were compared to untreated patients from a natural history cohort by assessing disease progression through Week 96 of treatment.[15] The investigators measured the loss of ability to walk or crawl using the Motor domain of the CLN2 Clinical Rating Scale.[15] Scores from the Motor domain of the scale range from 3 (grossly normal) to 0 (profoundly impaired).[15]

The U.S. Food and Drug Administration (FDA) requires the cerliponase alfa manufacturer to further evaluate the safety of cerliponase alfa in CLN2 patients below the age of two years, including device related adverse events and complications with routine use.[4] In addition, a long-term safety study will assess cerliponase alfa treated CLN2 patients for a minimum of ten years.[4]

The application for cerliponase alfa was granted priority review designation, breakthrough therapy designation, orphan drug designation, and a rare pediatric disease priority review voucher.[4] The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc.[4]

Structure and biomolecular mechanism

Mannose-6-phosphate molecules are added to oligosaccharides on cerliponase alfa amino acid residues to target the enzyme to the lysosome by binding mannose-6-phosphate receptors.

Cerliponase alfa is an approximately 59 kDa molecule made up of 544 amino acid residues in its proenzyme form, whereas the activated mature enzyme only contains 368 residues. Five of these residues have N-linked glycosylation sites.[16] These five residues have additional mannose-6-phosphate (M6P) targeting sequences which function to target enzymes to the lysosome. When the cerliponase alfa proenzyme reaches target neurons during administration, it binds mannose-6-phosphate receptors on the cell surface to trigger vesicle formation around the receptor-proenzyme complex.[17][18] The more neutral pH of the cytosol promotes binding of the proenzyme's M6P targeting sequences to their receptors. Once brought into the cell, the receptor-proenzyme complex vesicle is transported to the lysosome where the lower pH promotes both dissociation of the proenzyme from the receptor and activation of the proenzyme to its active catalytic form via cleavage of the proenzyme sequence.[17][19]

Like natural TPP1, cerliponase alfa functions as a serine protease, cleaving N-terminal tripeptides from a broad range of protein substrates. The enzyme uses a catalytic triad active site composed of the three amino acids, aspartic acid, glutamic acid, and serine. Serine functions as the amino acid that performs the nucleophilic attack during the ping pong catalytic activity of a serine protease.[20] The products of this reaction are a tripeptide and the remaining length of the protein substrate with a new N-terminal end that can be cleaved again. In CLN2 disease, TPP1 is deficient or not made at all, meaning that proteins are unable to be degraded in the lysosome and accumulate, leading to damage in nerves. As a protein, cerliponase alfa gets degraded by proteolysis.[16] Therefore, cerliponase alfa is administered repeatedly to maintain sufficient levels of the recombinant TPP1 enzyme in place of the deficient form to degrade proteins and prevent further build up. Cerliponase alfa is a treatment that can potentially slow disease progression but does not cure the disease itself.[17]

References

  1. ^ "Summary Basis of Decision (SBD) for Brineura". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. ^ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.
  3. ^ a b Markham A (July 2017). "Cerliponase Alfa: First Global Approval". Drugs. 77 (11): 1247–1249. doi:10.1007/s40265-017-0771-8. PMID 28589525. S2CID 25845031.
  4. ^ a b c d e f g h i j k l m n "FDA approves first treatment for a form of Batten disease". U.S. Food and Drug Administration (FDA) (Press release). 27 April 2017. Archived from the original on 10 December 2019. Retrieved 9 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  6. ^ Mole SE, Cotman SL (October 2015). "Genetics of the neuronal ceroid lipofuscinoses (Batten disease)". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease). 1852 (10 Pt B): 2237–41. doi:10.1016/j.bbadis.2015.05.011. PMC 4567481. PMID 26026925.
  7. ^ Sleat DE, Donnelly RJ, Lackland H, Liu CG, Sohar I, Pullarkat RK, et al. (September 1997). "Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis". Science. 277 (5333): 1802–5. doi:10.1126/science.277.5333.1802. PMID 9295267.
  8. ^ Gardner E, Bailey M, Schulz A, Aristorena M, Miller N, Mole SE (November 2019). "Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease". Human Mutation. 40 (11): 1924–1938. doi:10.1002/humu.23860. PMC 6851559. PMID 31283065.
  9. ^ "Cerliponase alfa (Brineura) – Ceroid lipofuscinosis 2 (CLN2 disease)". National Institute of Neurological Disorders and Stroke. Archived from the original on 13 July 2021. Retrieved 2 December 2019.
  10. ^ Mole SE, Anderson G, Band HA, Berkovic SF, Cooper JD, Kleine Holthaus SM, et al. (January 2019). "Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis". The Lancet. Neurology. 18 (1): 107–116. doi:10.1016/S1474-4422(18)30368-5. PMID 30470609. S2CID 53711337.
  11. ^ "European Commission Approves Brineura (cerliponase alfa), the First Treatment for CLN2 Disease, a Form of Batten Disease and Ultra-Rare Brain Disorder in Children". BioMarin. 1 June 2017. Archived from the original on 10 August 2017. Retrieved 23 July 2017.
  12. ^ "Evaluation consultation document: Cerliponase alfa for treating neuronal ceroid lipofuscinosis type 2". NICE. Retrieved 9 August 2018.
  13. ^ McKee S (13 February 2018). "NICE deems Batten disease therapy too costly for NHS use". Pharma Times. Retrieved 9 August 2018.
  14. ^ "FDA Approves BioMarin's Batten Disease Drug. Cost Per Year is $702,000". ChemDiv. 1 May 2017. Retrieved 2 December 2019.
  15. ^ a b c d e "Drug Trials Snapshot: Brineura". U.S. Food and Drug Administration (FDA). 25 May 2017. Archived from the original on 10 December 2019. Retrieved 9 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  16. ^ a b "Brineura- cerliponase alfa kit". DailyMed. 18 December 2018. Retrieved 9 December 2019.
  17. ^ a b c Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM (March 2019). "Therapeutic landscape for Batten disease: current treatments and future prospects". Nature Reviews. Neurology. 15 (3): 161–178. doi:10.1038/s41582-019-0138-8. PMC 6681450. PMID 30783219.
  18. ^ Mukherjee AB, Appu AP, Sadhukhan T, Casey S, Mondal A, Zhang Z, et al. (January 2019). "Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses". Molecular Neurodegeneration. 14 (1): 4. doi:10.1186/s13024-018-0300-6. PMC 6335712. PMID 30651094.
  19. ^ Kohlschütter A, Schulz A, Bartsch U, Storch S (April 2019). "Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses". CNS Drugs. 33 (4): 315–325. doi:10.1007/s40263-019-00620-8. PMC 6440934. PMID 30877620.
  20. ^ Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P (February 2009). "Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis". The Journal of Biological Chemistry. 284 (6): 3985–97. doi:10.1074/jbc.M806943200. PMC 2635056. PMID 19038967.

Read other articles:

The Chicks

American country band This article is about the American country band. For other uses, see The Chicks (disambiguation). The ChicksThe Dixie Chicks in Austin, Texas, in 2006Background informationAlso known asDixie ChicksOriginDallas, Texas, U.S.Genres Country[1] bluegrass[1] country pop[1] Years active1989–presentLabels Crystal Clear Sound Monument Nashville Columbia Nashville SpinoffsCourt Yard HoundsMembers Emily Strayer Martie Maguire Natalie Maines Past members Ro...

 

Latvijas Radio Amatieru Līga

Latvijas Radio Amatieru LīgaLatvian Amateur Radio LeagueAbbreviationLRALTypeNon-profit organizationPurposeAdvocacy, EducationLocationRiga, Latvia ​KO26bwRegion served LatviaOfficial language LatvianChairmanImants Tukleris YL3GCTAffiliationsInternational Amateur Radio UnionWebsitehttp://www.lral.lv/ The Latvijas Radio Amatieru Līga (LRAL) (in English, Latvian Amateur Radio League) is a national non-profit organization for amateur radio enthusiasts in Latvia. Key membership benefits of...

 

Club de Paris

Si ce bandeau n'est plus pertinent, retirez-le. Cliquez ici pour en savoir plus. Cet article ne cite pas suffisamment ses sources (juin 2017). Si vous disposez d'ouvrages ou d'articles de référence ou si vous connaissez des sites web de qualité traitant du thème abordé ici, merci de compléter l'article en donnant les références utiles à sa vérifiabilité et en les liant à la section « Notes et références » En pratique : Quelles sources sont attendues ? Comme...

ماجد هزازي

ماجد هزازي معلومات شخصية الاسم الكامل ماجد هزازي الميلاد 1 يوليو 1988 (العمر 35 سنة)الرياض الطول 172 سم مركز اللعب ظهير أيمن الجنسية السعودية  معلومات النادي النادي الحالي نادي الشعله الرقم 88 المسيرة الاحترافية1 سنوات فريق م. (هـ.) 1 عدد مرات الظهور مع الأندية وعدد الأهداف تحسب...

 

Gábor Pogány

Gábor Pogány (Budapest, 28 ottobre 1915 – Roma, 30 ottobre 1999) è stato un direttore della fotografia ungherese naturalizzato italiano. Indice 1 Biografia 2 Filmografia 3 Bibliografia 4 Altri progetti 5 Collegamenti esterni Biografia Nato in Ungheria a Budapest, frequenta la facoltà di Architettura della sua città. Dopo essersi laureato, si trasferisce in Inghilterra, occupandosi di fotografia legata al cinema sino a diventare aiuto operatore. Alla fine degli anni trenta arriva a Roma...

 

Anselm of St Saba

12th-century Bishop of London-elect Anselm of St SabaBishop of London electElectedabout 22 March 1136Installed1137Term ended1138PredecessorGilbert UniversalisSuccessorRobert de SigelloOther post(s)Abbot of Bury St. EdmundsOrdersConsecrationnever consecratedPersonal detailsDied3 January 1148DenominationCatholic Anselm[a] (died 1148) was a medieval bishop of London whose election was quashed by Pope Innocent II. He was a monk of Chiusa, abbot of Saint Saba in Rome, papal legate to ...

Adolf Hitler

Penyuntingan Artikel oleh pengguna baru atau anonim untuk saat ini tidak diizinkan.Lihat kebijakan pelindungan dan log pelindungan untuk informasi selengkapnya. Jika Anda tidak dapat menyunting Artikel ini dan Anda ingin melakukannya, Anda dapat memohon permintaan penyuntingan, diskusikan perubahan yang ingin dilakukan di halaman pembicaraan, memohon untuk melepaskan pelindungan, masuk, atau buatlah sebuah akun. Adolf HitlerPotret resmi, 1938 Führer JermanMasa jabatan2 Agustus 1934 –&...

 

B

  此條目介紹的是拉丁字母中的第2个字母。关于其他用法，请见「B (消歧义)」。   提示：此条目页的主题不是希腊字母Β、西里尔字母В、Б、Ъ、Ь或德语字母ẞ、ß。 BB b(见下)用法書寫系統拉丁字母英文字母ISO基本拉丁字母（英语：ISO basic Latin alphabet）类型全音素文字相关所属語言拉丁语读音方法 [b][p][ɓ](适应变体)Unicode编码U+0042, U+0062字母顺位2数值 2歷史發...

 

Galatama 1983–1984

Galatama IVMusim1983-1984Tanggal30 November 1983 s/d 20 Mei 1984JuaraYanita UtamaJumlah pertandingan347Jumlah gol444 (1,28 per pertandingan)Pencetak golterbanyak Bambang Nurdiansyah (13 gol)(Yanita Utama)← 1982-83 1984 → Galatama 1983-84 atau juga disebut Galatama IV adalah kompetisi Galatama musim ke 4. Ikhtisar Pada Galatama musim ini banyak perubahan-perubahan peraturan yang dibuat oleh PSSI diantaranya adalah. Larangan penggunaan pemain asing. Divisi I musim sebelumnya tidak ada ...

Raja Ramanna Centre for Advanced Technology

Raja Ramanna Centre for Advanced TechnologyAbbreviationRRCATFormation19 February 1984 (1984-02-19)PurposePhysicsHeadquartersIndore, Madhya PradeshLocationIndiaCoordinates22°40′01″N 75°48′32″E / 22.667°N 75.809°E / 22.667; 75.809Parent organisationDepartment of Atomic EnergyWebsitewww.rrcat.gov.in The Raja Ramanna Centre for Advanced Technology is a unit of Department of Atomic Energy, Government of India, engaged in R&D in non-nuclear fr...

 

Algernon Sidney

Ritratto di Algernon Sidney. Algernon Sidney (Castello di Baynard, 14 o 15 gennaio 1623 – 7 dicembre 1683) è stato un politico e nobile inglese. Teorico repubblicano, si oppose a Carlo II d'Inghilterra e rimase coinvolto in un complotto contro il re finendo giustiziato per tradimento. Indice 1 Biografia 2 Guerra civile inglese 3 Ambasciatore baltico 4 Esilio 5 Contro la monarchia 6 Processo ed esecuzione 7 Ascendenza 8 Opere 9 Note 10 Bibliografia 11 Voci correlate 12 Altri progetti 13 Col...

 

Private Bom

1948 film Private BomDirected byLars-Eric KjellgrenWritten byPaul Baudisch Nils Poppe Adolf SchützProduced byHarald MolanderStarringNils Poppe Inga Landgré Gunnar BjörnstrandCinematographyGunnar FischerEdited byOscar RosanderMusic byKai Gullmar Sune WaldimirProductioncompanyFribergs Filmbyrå ABDistributed byFribergs FilmbyråRelease date 15 December 1948 (1948-12-15) Running time89 minutesCountrySwedenLanguageSwedish Private Bom (Swedish: Soldat Bom) is a 1948 Swedish comed...

New Perspective (lagu)

New PerspectiveLagu oleh Panic! at the Discodari album Jennifer's Body: Original Motion Picture SoundtrackDirilis28 Juli 2009FormatUnduhan digitalDirekam2009Genre Pop punk power pop alternative rock pop rock Durasi3:47Label Fueled by Ramen Decaydance Pencipta Brendon Urie, John Feldman Produser Brendon Urie John Feldmann New Perspective adalah lagu milik grup musik rock asal Amerika Serikat, Panic! at the Disco yang dirilis pada 28 Juli 2009 sebagai singel promosi dari film Jennifer's Body. V...

 

安倍晋太郎

安倍晋太郎安倍晋太郎（攝於1987年4月21日） 日本第112、113任外務大臣任期1982年11月27日—1986年7月22日总理中曾根康弘前任櫻内義雄继任倉成正 日本第42任通商產業大臣任期1981年11月30日—1982年11月27日总理鈴木善幸前任田中六助（日语：田中六助）继任山中貞則 日本第41任内閣官房長官任期1977年11月28日—1978年12月7日总理福田赳夫前任園田直继任田中六助（日语�...

 

1999 Indian general election in Haryana

This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.Find sources: 1999 Indian general election in Haryana – news · newspapers · books · scholar · JSTOR (May 2019) (Learn how and when to remove this message) 1999 Indian general election in Haryana← 19982004 →10 seats   First party Second party Third party   Party...

История теории вероятностей

История теории вероятностей отмечена многими уникальными особенностями. Прежде всего, в отличие от появившихся примерно в то же время других разделов математики (например, математического анализа или аналитической геометрии), у теории вероятностей по существу не было ...

 

History of Uzbekistan

Map of Uzbekistan History of Uzbekistan Prehistory Teshik-Tash 1 Scythian Early history Sogdia Transoxiana Bactria Medieval history Turkic Khaganate Onoq Türgesh Tang Protectorate Muslim conquest Umayyad Caliphate Abbasid Caliphate Samanid Empire Ghaznavids Kara-Khanid Khanate Anushtegin dynasty Khwarazmian Empire Mongol conquest Chagatai Timurid Empire Uzbek Khanate Modern period Russian period Emirate of Bukhara Khorezm People's Soviet Republic Bukharan People's Soviet Republic Uzbek Sovi...

 

AQuantive

Defunct American public company aQuantiveWebsitewww.aquantive.com (offline) aQuantive, Inc. was the parent company of a group of three digital marketing service and technology companies: Avenue A/Razorfish, Atlas Solutions, and DRIVE Performance Solutions. Based in Seattle, Washington, the company was founded in 1997. According to Advertising Age magazine, in 2005 it ranked 14th by revenue among advertising agencies worldwide. On May 18, 2007, Microsoft announced that it would acquire the com...

丹尼斯·德米特里耶夫

丹尼斯·德米特里耶夫摄于2015年個人資料全名丹尼斯·谢尔盖耶维奇·德米特里耶夫出生 (1986-03-23) 1986年3月23日（38歲） 苏联梁赞州普龍斯克區特尔诺沃身高1.77米（5英尺10英寸）體重90公斤（200磅）車隊資料環境场地自行车 獎牌紀錄 男子自行车 代表 俄羅斯 奥林匹克运动会 2016 里约热内卢 个人竞速赛 世界場地自由車錦標賽 2017 香港 个人竞速赛 2013 明斯克 个人竞速�...

 

1898 год

Годы 1894 · 1895 · 1896 · 1897 — 1898 — 1899 · 1900 · 1901 · 1902 Десятилетия 1870-е · 1880-е — 1890-е — 1900-е · 1910-е Века XVIII век — XIX век — XX век 2-е тысячелетие XVII век XVIII век XIX век XX век XXI век 1790-е 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800-е 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1810-е 1810 1811 1812 1813 1814 1815 1816...