Cerliponase alfa

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Cerliponase alfa
Clinical data
Trade names Brineura
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Intraventricular
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Chemical and physical data
Formula C2657H4042N734O793S11
Molar mass 59308.57 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]

Contents

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. 3EE6.png
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. Mannose-6-phosphate.svg
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 that codes for 544 amino acids in its proenzyme form while the activated mature enzyme only codes for 368 amino acids. Five amino acid 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]

Related Research Articles

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Glycogen storage disease type II</span> Medical condition

Glycogen storage disease type II, also called Pompe disease, formerly known as GSD-IIa and LGMD2V. It is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. GSD-II and Danon disease are the only glycogen storage diseases with a defect in lysosomal metabolism, and Pompe disease was the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).

<span class="mw-page-title-main">Neuronal ceroid lipofuscinosis</span> Medical condition

Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.

Infantile neuronal ceroid lipofuscinoses (INCL) or Santavuori disease or Hagberg-Santavuori disease or Santavuori-Haltia disease or Infantile Finnish type neuronal ceroid lipofuscinosis or Balkan disease is a form of NCL and inherited as a recessive autosomal genetic trait. The disorder is progressive, degenerative and fatal, extremely rare worldwide – with approximately 60 official cases reported by 1982, perhaps 100 with the condition in total today – but relatively common in Finland due to the local founder effect.

<span class="mw-page-title-main">Glucocerebrosidase</span> Mammalian protein found in humans

β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism that is abundant in cell membranes. It is localized in the lysosome, where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.

BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme replacement therapies (ERTs). BioMarin was the first company to provide therapeutics for mucopolysaccharidosis type I, by manufacturing laronidase. BioMarin was also the first company to provide therapeutics for phenylketonuria (PKU).

<span class="mw-page-title-main">Battenin</span> Protein-coding gene in the species Homo sapiens

Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16. Battenin is not clustered into any Pfam clan, but it is included in the TCDB suggesting that it is a transporter. In humans, it belongs to the atypical SLCs due to its structural and phylogenetic similarity to other SLC transporters.

Iduronidase, sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan α-L-iduronohydrolase. It catalyses the hydrolysis of unsulfated α-L-iduronosidic linkages in dermatan sulfate.

Alglucosidase alfa, sold under the brand name Myozyme among others, is an enzyme replacement therapy (ERT) orphan drug for treatment of Pompe disease, a rare lysosomal storage disorder (LSD). Chemically, the drug is an analog of the enzyme that is deficient in patients affected by Pompe disease, alpha-glucosidase. It is the first drug available to treat this disease.

<span class="mw-page-title-main">Palmitoyl(protein) hydrolase</span> Class of enzymes

Palmitoyl protein hydrolase/thioesterases is an enzyme (EC 3.1.2.22) that removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. It catalyzes the reaction

<span class="mw-page-title-main">Tripeptidyl peptidase I</span> Protein-coding gene in the species Homo sapiens

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.

<span class="mw-page-title-main">CLN6</span> Protein-coding gene in humans

Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.

<span class="mw-page-title-main">CLN5</span> Protein-coding gene in humans

Ceroid-lipofuscinosis neuronal protein 5 is a protein that in humans is encoded by the CLN5 gene.

<span class="mw-page-title-main">CLN8</span> Protein-coding gene in humans

Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.

<span class="mw-page-title-main">PPT1</span> Protein-coding gene in the species Homo sapiens

Palmitoyl-protein thioesterase 1 (PPT-1), also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene.

<span class="mw-page-title-main">Jansky–Bielschowsky disease</span> Medical condition

Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown; however, NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.

<span class="mw-page-title-main">Northern epilepsy syndrome</span> Medical condition

Northern epilepsy syndrome (NE), or progressive epilepsy with mental retardation (EPMR), is a subtype of neuronal ceroid lipofuscinosis and a rare disease that is regarded as a Finnish heritage disease. Unlike most Finnish heritage diseases, this syndrome has been reported only in Finland. The disease is characterized by seizures in early childhood that progressively get worse until after puberty. Once the onset of seizures occurs, mental degradation is seen. This continues into adulthood, even after seizure frequency has decreased. The cause of the disease is a missense mutation on chromosome 8. The creation of a new protein occurs, and the lipid content of the brain is altered because of it. The ratio of the mutation carriers is 1:135. There is nothing that has been found to stop the progression of the disease, but symptomatic approaches, such as the use of benzodiazepines, have helped control seizures.

<span class="mw-page-title-main">MFSD8</span> Protein-coding gene in the species Homo sapiens

Major facilitator superfamily domain containing 8 also called MFSD8 is a protein that in humans is encoded by the MFSD8 gene. MFSD8 is an atypical SLC, thus a predicted SLC transporter. It clusters phylogenetically to the Atypical MFS Transporter family 2 (AMTF2).

Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs) or Batten disease. NCLs are broadly described to create problems with vision, movement and cognitive function. Among all NCLs diseases, Kufs is the only one that does not affect vision, and although this is a distinguishing factor of Kufs, NCLs are typically differentiated by the age at which they appear in a patient

References

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