Lutropin alfa - Luveris; human luteinizing hormone, recombinant; rhLH
Status - approved, marketed
Organizations involved:
Merck Serono S.A. – Manuf.; R&D; Tech.; Intl. mark.
EMD Serono, Inc. – USA mark.
Merck KGaA – Parent
Columbia University – Tech.; Patent dispute
Serono International S.A. – Former
Serono, Inc. – Former
Cross ref.: See the Follicle-Stimulating Hormone Products entry for further information about luteinizing hormone use in female infertility treatment. See also Pergoveris (#157), a new product combining Luveris with recombinant follitropin (Gonal-f; FSH).
Description: Luveris is a lyophilized (freeze-dried) formulation of lutroprin alfa or recombinant glycosylated human luteinizing hormone (LH) produced by a transformed Chinese hamster ovary (CHO) cell line. Lutroprin alfa is a heterodimeric glycoprotein consisting of two non-covalently linked subunits (designated alpha and beta) of 92 and 121 amino acids, respectively. Carbohydrate chain attachment to the r-hLH protein core (glycosylation) occurs via N- but not O-linkage. The N glycosylation sites are Asn-52 and Asn-78 for the alpha–subunit, and Asn-30 for the beta–subunit. The beta-chain has an N-glycosylation site and its structure and glycosylation pattern are very similar to that of human pituitary-derived luteinizing hormone.
Luveris is packages in vials for reconstitution with Sterile Water for Injection, USP, and subcutaneous (sc) injection. Each vial contains 82.5 IU lutropin alfa (for delivery of 75 IU), 48 mg sucrose, 0.83 mg dibasic sodium phosphate dihydrate, 0.052 mg monobasic sodium phosphate monohydrate, 0.05 mg polysorbate 20 (Tween 20), and 0.1 mg L-methionine. Phosphoric acid and/or sodium hydroxide are used to adjust the pH. After reconstitution with 1 mL of the enclosed diluent, the product delivers 75 IU of human lutropin alfa at a pH of 7.5-8.5.
Luveris is the first recombinant luteinizing hormone, offering advantages in purity and consistency, allowing physicians to customize dosing for their patients. Other LH products, including those in the U.S. market, are derived from the urine of menopausal women, contain impurities and their contents may not be consistent from batch-to-batch.
Nomenclature: luteinizing hormone, rDNA [BIO]; Luveris [TR]; lutropin alfa [USAN INN]; r-hLH [SY]; human luteinizing hormone, recombinant [SY]; rhLH [SY]; NDC 44087-1375-1 [NDC]
Biological.: LH can be cleaved to yield two dissimilar subunits, α-LH and β-LH. Taken separately, these hormonal subunits exhibit very little of the biological activity associated with whole molecule LH. Each α-subunit (approximate molecular weight of 13,500 Daltons) is virtually identical to the α-subunits of the related pituitary hormones, FSH and TSH, and the the placental hormone hCG. The biological activity of LH is dependent on the distinct make-up of the β-subunit (approximate molecular weight of 14,500 Daltons), which differs in amino acid sequence from the β-subunits of FSH, TSH, and hCG.
Luveris is used for treatment of women with an endocrine form of infertility characterized by a severe LH and follicle stimulating hormone (FSH; see related entries) deficiency. Luveris (or another LH product) is used in combination with FSH, such as recombinant FSH (Gonal-f; also from Merck Serono), for the stimulation of follicles (to produce eggs) in the ovaries. See the Follicle Stimulating Hormone Products and Gonal-f entries for further information about infertility treatment.
The biological activity of lutropin alfa is determined using the Van Hell Bioassay, as described in the British Pharmacopoeia. The in vivo biological activity is determined using an in-house standard properly calibrated against the relevant international standard.
Companies.: Luveris was developed, originally manufactured and marketed internationally (not in the U.S.) by Serono International S.A. and affiliates. In Jan. 2007, Merck KGaA acquired Serono, and the new company was renamed Merck Serono S.A. Serono, Inc., now EMD Serono, Inc., markets Luveris in the U.S.
Manufacture: manufacture involves conventional expansion of genetically modified large scale cell culture of Chinese Hamster Ovary (CHO) cells from an extensively characterized cell bank. Lutropin alfa is secreted by the CHO cells directly into the cell culture medium, and is purified using a series of chromatographic steps.
The gene for the alpha-subunit of LH was isolated frm a bacteriophage lambda library containing human fetal liver genomic DNA. The beta-subunit gene was isolated from a plasmid pBR322 library containing human pituitary cDNA. Since the intact 5’ sequence could not be isolated, a complete gene was constructed by insertion of a small portion of the hCG beta-subunity fragment (since the hCG and LF beta-subunits are similar), with this including the ATG start codon and the first 12 amino acids of the secretory signal peptide for the beta-subunit of LH. The expression vectors used had a bacterial origin of replication, allowing maintenance in E. coli K12, along with the mouse metallothienein-I gene promoter sequence for constitutive expression of the inserted sequence and the SV40 early polyadenylation signal sequence. The dihydrofolate reductase (DHFR) selectable marker on the alpha subunit vector was used to isolate transfected cell by culture in the presence of methotrexate (which is toxic to untransformed, DHRf-, cells). These vectors were stably transfected in a standard Chinese hamster ovary (CHO) cell line for expression of rLH with structure corresponding to the native glycoprotein, including N-terminal heterogeneity in both subunits and truncated forms of teh C-terminus of the beta-subunit.
FDA class: Drug NDA
Approvals: Date = 20040501; NDA (no. 21-322)
indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
Luveris (lutropin alfa for injection), concomitantly administered with Gonal-f (follitropin alfa for injection), is indicated for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH < 1.2 IU/L). A definitive effect on pregnancy in this population has not been demonstrated. The safety and effectiveness of concomitant administration of Luveris with any other preparation of recombinant human FSH or urinary human FSH is unknown.
Selection of Patients: 1. Patients should have baseline serum hormone levels of LH < 1.2 IU/L and FSH < 5 IU/L. 2. Before treatment with gonadotropins is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy and exclusion of pregnancy. 3. Patients should have a negative progestin challenge test 4. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Luveris and follitropin alfa therapy. 5. Evaluation of the partner’s fertility potential should be included in the initial evaluation.
Status: Luveris received European Union approval in Dec. 2000, and was launched in the first half of 2001.
The NDA for FDA approval was submitted on May 1, 2001, and accelerated approval was granted on Oct. 8, 2004 (approval time = ~41.3 months) with orphan drug designation. Approval was granted under Subpart H [21 CFR 314.510 (Subpart H)], i.e., based on a surrogate endpoint(s) or on an effect on a clinical endpoint other than survival or irreversible morbidity.
In July 2011, Luveris received European Union supplemental approval for packaging in prefilled pen injectors (300 IU, 450 IU and 900 IU) designed to increase compliance during fertility treatment. After administration the pens immediately confirm if a complete dose was delivered. If an incomplete dose was delivered the pen informs the user of the missing amount.
Tech. transfer:
U.S. 7,151,083, "Luteinizing hormone and follicle stimulating hormone for use in inducing folliculogenesis," is a use patent assigned to Serono, expires May 5, 2020.
No relevant EP patents were identified, including scanning all patents with "hormone" in the title or abstract assigned to Serono
Serono was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Serono and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
Medical: Luveris is used in combination with a follicle-stimulating hormone (FSH), such as Gonal-f (see related entry) from Merck Serono, for the stimulation of production of follicles or eggs in the ovaries. Prior to launch of Luveris in Europe (and still in the U.S.), LH was only available as urine-derived human menopausal gonadotropins (hMG) preparations containing varying amounts of several other impurities. Luveris allows physicians to individualize dosing of pure LH and FSH for the first time, offering greater treatment flexibility. Luveris is administered by subcutaneous injection.
Disease: Hypogonadotropic hypogonadal (HH) with profound LH deficiency (LH < 1.2 IU/L) resulting in infertility is a rare disease in women. Women with HH are unable to produce the hormones (LH and FSH) needed for full development of follicles in the ovaries, ovulation, and growth of the lining of the uterus sufficient to support implantation of a fertilized egg and early pregnancy. Luveris provides an option to attain fertility for women who specifically do not produce or secrete LH. Multiple births may result from LH and other gonadotropin treatments
Market: The 2007 Average Wholesale Price (AWP) is $29.26 for each 75 IU vial (Red Book, 2007). The 2005 AWP was $27.60.
Luveris is not a major product for Serono (Merck Serono). Total sales in 2004 were only $10.6 million, and $10 million in 2003. The author’s crude guess for 2006 sales is ~$30 million.
With the U.S. launch of Luveris, Serono became the only company offering all three products that are needed to treat infertility in recombinant form – follicle stimulating hormone (FSH; Gonal-f); human choriogonadotropin (hCG; Ovidrel); and human luteinizing hormone (Luveris). This complete portfolio of infertility products is now globally available with the exception of Japan. See these other entries and, particularly, the Follicle Stimulating Hormone Products and Gonal-f entries, for further information about infertility treatment.
R&D: AspenBio Pharma, Inc. is developing StayBred containing a recombinant single-chain LH analog licensed from Washington University designed to help dairy cows maintain pregnancy, thereby increasing milk production and reducing overall reproduction costs.
Companies involvement:
Full monograph
228 Luteinizing Hormone, rDNA
Nomenclature:
luteinizing hormone, rDNA [BIO]
Luveris [TR]
lutropin alfa [USAN]
human luteinizing hormone, recombinant [SY]
r-hLH [SY]
rhLH [SY]
NDC 44087-1375-1 [NDC]
molecular weight (kDa) = 28
FDA Class: Drug NDA
Year of approval (FDA) = 2004
Date of 1st FDA approval = 20040501
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2020, based on 7,151,083 use patent |
U.S. Patent Expiration Year: | |
U.S. Biosimilars Data Exclusivity Expiration: | 2016 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2011 |
U.S. Biosimilars Launchability Year: | 2020 |
U.S. Biobetters Launchability Year: | 2020 |
Biosimilars/biobetters-related EU Patents: | No relevant patents identified. |
EU Patent Expiration Year: | |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
hormones
hormones
recombinant DNA
rodent source materials
yeast source materials
yeast source materials
Chinese hamster ovary (CHO) cells
rodent cells <!-- rodentcells -->
Saccharomyces cerevisiae (yeast)
lyophilized (freeze-dried)
methanol
phosphoric acid
polysorbate 20 (Tween 20)
sodium hydroxide
sodium phosphate, dibasic
sodium phosphate, monobasic
sucrose
accelerated approval (based on surrogate endpoints) (FDAapproved)
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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