rDNA, PEG-
pegvisomant - Somavert; somatropin (human growth hormone) antagonist, pegylated, recombinant;
Status: approved; marketed
Organizations involved:
Pfizer Corp. – R&D; Tech.; World mark.; Parent
Pharmacia Corp. – Former
Sensus Drug Dev. Corp. – R&D; Tech.; Former
Genentech, Inc. – R&D; Tech.
Fuji Diosynth RTP, Inc. – Manuf.
Akzo-Nobel N.V. – Former
Abbott Laboratories, Inc. – Manuf. other
Shearwater Corp. – Tech; Former
Nektar Therapeutics, Inc. – Tech.
Inhale Therapeutic Systems, Inc. – Parent
University of Alabama – Tech.; Patent dispute
Description: Pegvisomant or Somavert is a lyophilized (freeze-dried) formulation of B2036, a mutein (modified version) of human growth hormone (hGH; somatropin) protein with nine amino acid substitutions, expressed by Escherichia coli (E. coli) bacteria covalently conjugated to 4-5 polyethylene glycol (PEG) polymer side chains. B2036 was designed to act as an antagonist (inhibitor) of cellular somatropin receptors by substitution of of certain amino acids in the backbone of human somatropin, and attachment of PEG side chains to increase the molecule’s in vivo half life. Somavert, as an somatotropin antagonist, is used for treatment of acromegaly or disease due to excess endogenous somatotropin. Somavert is the first growth hormone receptor antagonist to receive approval.
The B2036 (somavert) protein, like endogenouse hGH, consists of 191 amino acids with two internal disulfide bonds between cysteine residues (Cys59-Cys165; Cys182-Cys198) and four regions of alpha-helical structure, with a molecular weight of 21,998 Daltons (~22 kDa). B2036 is hGH with the following amino acid substitutions: H18D, H21N, G120K, R167N, K168A, D171S, K172R, E174S, I179T. These substitutions increase binding affinity for the hGH cellular receptor at Site 1. Somatotropin variants including any one of these sets of amino acid substitutions act as hGH agonists (inhibitors) in the absence of any additional modification that disrupt binding to the hGH receptor at Site 2. The substitution of a different amino acid at G120 is a key modification that disrupts Site 2 binding, with hGH variants including a substitution at G120 acting as an hGH antagonist.
Pegylation of B2036 results in PEG-B2036 (pegvisomant; B2036-PEG) with four to five PEG side chains attached to varying sites on each B2036 protein molecule. The molecular weight of the PEG portions of pegvisomant is ~5,000 Daltons (5 kDa). The predominant molecular weights of pegvisomant are approximately 42,000, 47,000, and 52,000 Daltons (43, 47, and 52 kDa). The main PEG attachment sites on B2036 are Phe1, Lys38, Lys41, Lys70, Lys115, Lys120, Lys140, Lys145, and Lys158. PEGylation is believed to slow renal clearance by providing increased hydrodynamic volume in pegylated proteins.
Somavert is packaged in single-dose vials containing 21, 32, or 43 mg of pegvisomant, equivalent to 10, 15, and 20 mg of B2036 protein (with approximately 10, 15, and 20 U activity, respectively), for subcutaneous injection. Vials also contain 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium phosphate monobasic monohydrate. Prior to use, Somavert is reconstituted with 1 mL of Sterile Water for Injection supplied in a 8 mL vial. The product does not contain any components of animal or human origin, or any preservatives. Somavert is stored at 2-8˚C (refrigerated).
Nomenclature: Somatropin antagonist, rDNA, PEG- [BIO]; pegvisomant [FDA INN]; Somavert [TR]; somatotropin [18-aspartic acid, 21-asparagine, 120-lysine, 167-asparagine, 168-alanine, 171-serine, 172-arginine, 174-serine, 179-threonine] (human), pegylated [CAS]; 218620-50-9 [CAS RN]; human growth hormone antagonist, PEG-, rDNA [SY]; somatropin antagonist, pegylated, recombinant [SY]; PEG-B2036 [SY]; B2036-PEG [SY]; B-2036 [SY]; Trovert [SY]; PNU-467-MET-0435 [SY]; NDC 0009-5178-01; NDC 0009-5176-01; NDC 0009-5180-01 [NDC]
Biological.: The B2036 protein portion of pegvisomant binds to somatropin (hGH) receptors on cell surfaces, but has no somatropin activity. This blocks the binding and activity of endogenous human somatropin (hGH), interfering with intracellular growth hormone signaling. Phage display experiments were used to screen for hGH residue replacements that would increase binding affinity for the hGH receptor, resulted in B2036 (B-2036) with nine amino acid substitutions relative to hGH, with one in binding site 2 and eight in binding site 1 of hGH. This mutein specifically bind to hGH receptor and is internalized, but does not induce functional dimerization of hGH receptor. The affinity of B2036 for hGH receptor is comparable to that of endogenous hGH. Attachment of 4-5 polyethylene glycol (PEG) polymer strands to B2036, forming pegvisomant, reduces its binding affinity for hGH receptor by 30-40 fold. This requires a higher dose for comparable activity, but the benefits of pegylation make up for this, e.g., significantly reducing its in vivo degradation and kidney clearance.
B2036 has high affinity for one cellular somatropin binding site (Site 1) and low affinity for a second binding site (Site 2), which activates cellular signaling. Binding of B2036 or pegvisomant to somatropin Site 1 receptors enables dimerization of the growth hormone receptor at the cell surface, blocks endogenous somatropin from binding to and displaces somatropin bound to the cellular receptors, and prevents the conformational changes for needed for cell signalling. Pegylation of B2036 decreases its hGH receptor antagonist activity, but the longer in vivo half-life (reduced rate of clearance) of the conjugate more than makes up for this with longer activity (and efficacy).
The goal of administration of pegvisomant is to normalize serum concentrations of insulin growth factor-1 (IGF-1), which correlate with acromegaly disease activity and serum somatropin levels, leading to improvements in metabolic disorders (diabetes and glucose intolerance) in acromegalic patients. Administration of pegvisomant leads to decreased serum concentrations of IGF-1 and other somatropin-responsive serum proteins, including free IGF-1, the acid-labile subunit of IGF-1 (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3). All known activities of somatropin, including indirect effects, are mediated via the cellular somatropin receptor (bound/blocked by pegvisomant). Pegvisomant is highly selective for the somatropin receptor, e.g., it does not bind prolactin receptor, despite sequence homology between somatropin and prolactin. The activity of pegvisomant is independent of pituitary tumor activity, because it blocks somatropin at the cellular level, reducing the action of somatropin rather than inhibiting its secretion. Biological potency is determined using a cell proliferation bioassay.
Pegylation of B2036 increases the serum half-life of the resulting conjugate and extends to activity of the B2036 component. The PEG side chains sterically inhibit the approach of proteolytic enzymes and reduce excretion by the kidneys. Pegvisomant has an estimated serum half-life of 74-172 hours.
Companies.: Somavert was originally developed by Sensus Drug Development Corp., which in March 2001 was acquired by Pharmacia Corp. , which in May 2003 was acquired by Pfizer Corp. Somavert is marketed in the U.S. by Pharmacia/Pfizer, and and internationally by Pharmacia/Pfizer affiliates. B2036 bulk protein is manufactured and its pegylation is performed under contract to Pharmacia by Diosynth RTP Inc., formerly owned by Akzo-Nobel N.V., now Fuji Diosynth. Formulation, lyophilization, and packaging are performed by Abbott Laboratories, Inc. under contract to Pharmacia/Pfizer.
Pegylation technology has been licensed from Nektar Pharmaceuticals.
In Sept. 2011, Pfizer announced a $200 million expansion of its Grange Castle, Ireland, manufacturing facility, including a new pegylation production facility for Macugen and Somavert.
Manufacture: B2036 protein is produced by fermentation (culture) of E. coli 33B6 host strain containing an expression cassette for B2036. A Master Cell Bank (MCB) using a selected clone has been established. B2036 is initially expressed as a fusion protein with a 23-amino acid leader peptide sequence. This is exported from the cytoplasm into the periplasmic space, with cleavage of the leader peptide, and oxidation of the two disulfide bonds. Purification consists of a sequence of chromatography and ultrafiltration steps providing bulk protein solution.
B2036 is reacted with a 5 kDa methoxy-polyethylene glycol polyer (mPEG) chain with a terminal N-hydroxysuccinimide (NHS) active ester group that is highly reactive toward primary amines. mPEG chains (straight, not branched) are attached at multiple positions in the protein through stable amide linkages with Lysines and the N-terminal amino acid. Monofunctional PEG capped with methoxy group (mPEG) covalent attachment to B2036 (pegylation) minimizes crosslinking (aggregation); results in a “cloud” of PEG polymer around the protein, protects it from enzymatic degradation; binds water, increases hydrodymamic volume; and reduces kidney clearance PEGylation results in a heterogeneous product (variable number and positions of PEG side chains). See the peginterferon alfa-2a (Pegasys) entry for further discussion of pegylation. Heterogeneity is reduced by further purification to predominantly provide molecules with 4-5 side chains.
API tests adopted for release of Somavert are appearance; pH; osmolality; UV absorbance; tryptic mapping; SDS-PAGE (Ag); size exclusion HPLC; ion exchange HPLC; reverse phase HPLC (RP-HPLC); hydrophobic interaction HPLC; capillary electrophoresis; potency by cell proliferation assay; bioburden; endotoxin; and host cell protein assay.
FDA class: Drug NDA
Approvals: Date = 20030326; NDA (NDA 21-106); first approval; orphan drug status (expires 3/2010)
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
Somavert is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum IGF-I levels.
Status: The NDA for Somavert was filed by Sensus prior to its acquisition by Pharmacia (Pfizer) in March 2001. Pharmacia received an “Approvable” letter from FDA in June 2001 citing 16 CMC (chemistry-manufacturing-control) deficiencies, with multiple subpoints, needing to be addressed prior to approval. This included improving analytical capabilities for evalulating product quality and stability; optimization of methods for evaluating the PEGylation profile; and the need to purify the heterogenous pegylated B2036 to >90% purity.
On March 26, 2003, Somavert received FDA approval. Somavert was launched in the U.S. in June 2003, becoming the first therapeutic available for treatment of acromegaly in patients having failed or not able to receive other treatments.
Somavert was approved in the European Union (EU) in Oct. 2003 and launched in Nov. 2003 for the treatment of patients with acromegaly having an inadequate response to surgery and/or radiation therapy and in whom an appropriate medical treatment with somatostatin analogs did not normalize IGF-I concentrations or was not tolerated.
Tech. transfer: Sensus originally licensed Somavert from Genentech. The product insert/labeling cites U.S. patent 5,849,535, “Human growth hormone variants,” assigned to Genentech, Inc., including claims describing B2036/pegvisomant. Related patents assigned to Genentech, Inc. include 6,136,563, “Human growth hormone variants comprising amino acid substitutions,” a continuation of 5,849,535; and also 6,057,292 and 6,004,931, both entitled, “Method for inhibiting growth hormone action.” These patents claim somatropin muteins optimized for somatropin receptor binding (blockage), including B2036 and its specific amino acid substitutions, and use for treatment of acromegaly.
U.S. patents 5,958,879; 5,681,809; 5,849,535; 6,057,292; 5,350,836; and 6,583,115 assigned to Pfizer expired on
Sep 27, 2011 (Orange Book).
EP1568771, EP0851925 and EP1568772, "Human growth hormone variants," expire in 2016,
Pegylation technology was licensed, originally by Sensus, from Shearwater Corp., now Nektar Therapeutics, Inc., a subsidiary of Inhale Therapeutic Systems, Inc. See the peginterferon alfa-2a (Pegasys) entry for further discussion of pegylation-related patents.
In July 2006, the University of Alabama (Huntsville, AL; UAH) settled a patent dispute brought against Nektar and its original founder, Dr. Milton Harris, formerly with the university, receiving a cash payment of $25 million. Nektar and Dr. Harris jointly made an upfront payment totaling $15 million to UAH; and Nektar will pay UAH $1 million/year for ten years. UAH dismissed all claims related to the Nektar’s PEGylation patent portfolio and Nektar dismissed all counterclaims. UAH had sued Nektar in U.S. District Court for patent infringement, breach of contract license, violation of the Alabama Trade Secrets Act and unjust enrichment. Dr. Harris and another researcher developed a PEGylation technology, which was patented by UAH (U.S. 5,252,714, “Preparation and use of polyethylene glycol propionaldehyde “). The university had entered into a royalty agreement with Dr, Harris for products developed from this discovery, and Harris created Shearwater Polymers, now Nektar. UAH claimed that Harris, without UAH’s knowledge, made a number of other discoveries related to the PEG technology in the following years, patented 28 of them, that Harris was required to notify UAH of any discovery related to the original PEG patent, and that the patents were “obvious derivatives” of and “equivalent” to the original UAH PEG patent.
Disease: Acromegaly is a serious debilitating disease caused by a noncancerous tumor on the pituitary gland resulting in secretion of increased quantities of human growth hormone (somatropin). This can result in abnormal growth of hands and feet, changes in face shape, swelling, headaches, hypertension, diabetes, excessive sweating, soft-tissue swelling, joint disorders, and other related symptoms. Perhaps most striking is the progressive coarsening of facial features and enlargement of the hands, feet, and jaw. Approximately 40,000 people in the U.S. Europe, and Japan have acromegaly. About half of these cases can be cured surgically. Patients with acromegaly have a mortality rate 2-4 times higher than the average person, due to serious long-term complications including heart and respiratory disease, diabetes mellitus, and some forms of cancer.
Trials: Somavert was studied in a pivotal, fixed-dose, randomized, placebo-controlled, 12-week, 112-patient clinical trial; and in a open-label, adjusted-dose, 38-patient, 12-month study. IGF-I levels were used as a surrogate marker for the severity of acromegaly. In its Phase III trials, Somavert showed 89% efficacy as measured by normalization of IGF-I levels. In the pivotal study, serum IGF-I concentrations were reduced from baseline in all three groups treated with Somavert compared with placebo, and were normalized in 82% of patients at the 20 mg/day dose. In the long-term study, 92% (35/38) achieved a normal serum IGF-I concentration within age-adjusted ranges.
Medical: A loading dose of 40 mg is generally administered under medical supervision. The patient then begins daily subcutaneous self-injection of 10 mg. Serum IGF-I concentrations should be measured every 4-6 weeks, at which time the dosage can be adjusted in 5-mg increments to maintain IGF-1 within the age-adjusted normal range.
Currently, the first choice for treatment of acromegaly is surgical removal (and/or radiation therapy) of the somatropin-secreting tumor. For patients not responding, for whom surgery is contraindicated, or waiting for radiotherapy to become effective, somatostatin analog drugs and dopamine type 2 (D2) antagonosts are administered, with these drug indirectly decreasing somatropin secretion. Somavert provides an alternative for patients not responding to somatostatin analogs.
Market: The 2007 Average Wholesale Price (AWP) is $90.00/10 mg vial; $135.00/15 mg vial; and $180.00/20 mg vial (Red Book, 2007). These AWPs are unchanged from 2004.
Pfizer does not report annual sales of Somavert. The author’s rough guess for 2005 worldwide sales is $110-$150 million (assuming 4,000 patients or 10% of acromegaly patients consume 10 mg daily or 180 20-mg vials/year, ~$32,400/patient, at the AWP).
In Aug. 2004, the Centers for Medicare & Medicaid Services (CMS) added Somavert coverage under the Medicare replacement drug demonstration project, under which Medicare pays for certain therapeutics that patients can administer at home and involving therapeutics that replace those currently covered under Medicare Part B when administered in a doctor’s office. Generally, self-administered drugs have not been reimbursed by Medicare.
Companies involvement:
Full monograph
259 Somatropin antagonist,
Nomenclature:
Somatropin antagonist, rDNA, PEG- [BIO]
Somavert [TR]
pegvisomant [FDA INN]
somatotropin [18-aspartic acid, 21-asparagine, 120-lysine, 167-asparagine, 168-alanine, 171-serine, 172-arginine, 174-serine, 179-threonine] (human), pegylated [CAS]
B-2036 [SY]
B2036-PEG [SY]
human growth hormone antagonist, PEG-, rDNA [SY]
PEG-B2036 [SY]
PNU-467-MET-0435 [SY]
somatropin antagonist, pegylated, recombinant [SY]
Trovert [SY]
NDC 0009-5176-01 [NDC]
NDC 0009-5178-01 [NDC]
NDC 0009-5180-01 [NDC]
molecular weight (kDa) = 22
FDA Class: NDA Drug
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20030325
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2011, according to Orange Book |
U.S. Patent Expiration Year: | |
U.S. Biosimilars Data Exclusivity Expiration: | 2015 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2010 |
U.S. Biosimilars Launchability Year: | 2015 |
U.S. Biobetters Launchability Year: | 2011 |
Biosimilars/biobetters-related EU Patents: | 2016, based on EP1568771, EP0851925 and EP1568772 |
EU Patent Expiration Year: | 2016 |
EU Biosimilars Data Exclusivity Expiration: | 2013 |
EU Biosimilars Orphan Exclusivity Expiration: | 2013 |
EU Biosimilars Launchability Year: | 2016 |
EU Biobetters Launchability Year: | 2016 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
Holt's media, modified
recombinant DNA
bacterial culture <!-- bacterialculture -->
fusion proteins, recombinant
autologous cells, human
glycine
lyophilized (freeze-dried)
polyethylene glycol (PEG)
sodium phosphate, dibasic
sodium phosphate, monobasic
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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