Somatropin (rDNA origin) - Saizen; Serostim; Zorbtive; human growth hormone, recombinant
Status - approved; marketed
Organizations involved:
EMD Serono, Inc. – Manuf.; R&D; Tech.; USA Mark.
Merck Serono S.A. – Intl. mark.; Parent
Merck KGaA – Parent
Savient Pharmaceuticals, Inc. – USA mark.; Former
Bio-Technology General Corp. – Former
Bioject Medical Tech., Inc. – Manuf. other; Tech.
Novo Nordisk Pharmaceuticals, Inc. – Patent Dispute
Lonza Biologics plc – Tech.
University of Glasgow – Tech.
Celltech Biologics plc – Tech; Former
Columbia University – Tech.; Patent dispute
Serono, Inc. – Former
Serono International S.A. – Former
Cross ref.: See the Somatotropin (hGH) Products entry, and the other somatropin product entries.
Description: Somatropin (rDNA Origin) for Injection from Serono Laboratories Inc. refers to three different branded products, Serostim LQ, Saizen and Zorbtive, each containing identical recombinant human growth hormone (rhGH) expressed by transformed murine tumor cell line C-127 (C127), but marketed for different indications: in different formulations/presentations. This is the only mammalian cell expressed rhGH marketed in the U.S. The amino acid sequence, structure, including disulfide bridges, properties, activity and therapeutic efficacy of this mammalian cell expressed hGH are essentially identical to the dominant form of human pituitary growth hormone (and other E. coli-expressed hGH products, except for somatrem/Protropin).
The three branded products (Serostim LQ, Saizen and Zorbtive) are packaged differently and their uses/indications: and dosage regimens are much different. Serostim LQ is an aqueous formulation marketed only for AIDS cachexia (wasting)-related indications:. Saizen is marketed for growth hormone deficiency-related indications:. Zorbtive is marketed for short bowel syndrome. Both Saizen and Zorbtive are lyophilized (freeze-dried) formulations. In vitro, preclinical, and clinical testing have demonstrated that the recombinant hGH in these products are therapeutically equivalent to normal human pituitary-derived hGH. Clinical studies in adults have demonstrated comparable pharmacokinetics for the hGH in Saizen/Serostim/Zorbtive with human pituitary hGH. Therapeutic effects of Saizen on growth in children are comparable to those of other E. coli expressed recombinant hGH products, both with and without terminal methionine.
Serostim is was originally packaged as a lyophilized powder in single-dose vials each containing 4 mg (~12 IU; 3 IU/mg), 5 mg (~15 IU), or 6 mg (~18 IU) somatropin, along with Sterile Water for Injection, for subcutaneous or intramuscular injection. Vials also contained 6.825 mg sucrose and 0.225 mg phosphoric acid per mg somatropin. The pH was adjusted with sodium hydroxide or phosphoric acid to 7.4 to 8.5 (after reconstitution). Prior to use, each 4, 5, or 6 mg vial of Serostim was reconstituted with 1 mL of Sterile Water for Injection, USP (unlike Saizen which is reconstituted with 10 mL of bacteriostatic water).
Serostim LQ, an aqueous formulation, of Serostim was approved in early 2005. Serostim LQ is packaged in 6 mg cartridges for single dose administration. Each cartridge contains 0.5 mL of 8.16 mg (approximately 18 IU) somatropin, 1.02 mg Poloxamer 188, 40.8 mg sucrose, 1.31 mg citric acid, and Water for Injection USP q.s. to 0.68 g. The pH is adjusted with sodium hydroxide to a pH of 5.85 ± 0.1. Upon expiration, Serostim LQ may contain up to 18% hGH-related proteins.
Saizen is packaged as a 5 mg single-dose vial, along with a vial containing 10 mL of Bacteriostatic Water for Injection, USP. Each vial contains 5.0 mg (~15 IU) somatropin at a concentration of 3 IU/mg, 34.2 mg sucrose and 1.2 mg O-phosphoric acid. Saizen is intended for subcutaneous or intramuscular injection after reconstitution with 10 mL of Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol as a preservative).
Zorbtive is packaged in 8.8 mg vials for multi-dose administration. Each vial contains 8.8 mg (~26.4 IU) somatropin, 60.19 mg sucrose, and 2.05 mg phosphoric acid; along with a 10 mL vial of Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol as preservative).
The lyophilized presentations (Saizen and Zorbtive) vials should be stored at room temperature (15-30˚C). The pH of lyophilized somatropin vials is adjusted with sodium hydroxide or phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution. Serostim LQ cartridges should be stored at 2-8˚C (refrigerated), and the expiration date is printed on the label.
In Feb. 2002, Serono launched the SeroJet Needle-Free Device for delivery of Serostim. Developed and manufactured by Bioject Medical Technologies, Inc., SeroJet uses a coiled spring mechanism to deliver a finely dispersed high-pressure stream of Serostim through a point of entry in the skin that is five times smaller in area than that of a standard 28-gauge needle injection. This was the first needle-free somatotropin delivery system in the U.S. SeroJet is offered at no additional cost to Serostim patients, but patients must first be trained in its use.
Nomenclature: Somatropin, rDNA/Merck Serono [BIO]; Saizen [TR for hGH deficiency]; Serostim [TR for AIDS-related cachexia]; Zorbtive [TR for short bowel syndrome]; Somatropin (rDNA origin) for injection [FDA]; Somatropin (human) [CAS]; 12629-01-5 [CAS RN]; human growth hormone, recombinant [SY]; rhGH [SY]; hGH [SY]; somatomammotropin [SY]; cool.click [TR for injector]; Click.easy [TR for reconstitution device]; One.click [TR for injector]; NDC 44087-1005-2 [NDC for Saizen; NDC 44087-0004-7, NDC 44087-0005-7, NDC 44087-0006-7 [NDC for Serostim [NDC]; NDC 44087-3388-7 [NDC for Zorbtive]; NDC 44087-1006-1 and NDC 44087-1006-7 [NDC for Serostim LQ]
Biology: See the Somatropin Products entry. Zorbtive is the only hGH product available for short bowel syndrome. Intestinal mucosa contains receptors for hGH and insulin-like growth factor-1 (IGF-1), which mediates many of the cellular actions of hGH. In clinical studies, administration of hGH has been shown to enhance the transmucosal transport of water, electrolytes, and nutrients. The actions of hGH on the gut may be direct or mediated via the local or systemic production of IGF-1.
Companies.: Saizen, Serostim, and Zorbtive were developed and are manufactured by Serono Laboratories Inc. (Westborough, MA), a subsidiary of Ares-Serono S.A. In Jan. 2007, Merck KGaA acquired Serono, and the new company was renamed Merck Serono S.A. The products are marketed in the U.S. by EMD Serono, Inc. (previously Serono, Inc.), and internationally by Merck Serono S.A. and affiliates. An additional manufacturing facility, Farmaceutica Serono S.p.A (Bari, Italy) was approved in 2004.
Bio-Technology General Corp. (BTG), later Savient Pharmaceuticals, Inc., concluded an agreement to co-market Saizen in the U.S. in May 1998. However, BTG never started U.S. marketing, and received approval for its own hGH. This caused Serono to bring suit against BTG/Savient. See the Tev-Tropin entry for further information about BTG/Savient’s efforts to market its own rhGH, Tev-Tropin, in the U.S. [Note, the biopharmaceuticals business of Savient was acquired by Ferring BV in mid-2005].
The cool.click injector was developed for Saizen in partnership with Bioject Medical Technologies, Inc., a leading developer and manufacturer of jet injection systems for needle-free drug delivery, through an exclusive license agreement announced in Jan. 2000. The device was customized and tested for use with Saizen, and is sold under the Merck Serono brand. The SeroJet injector, also developed and manufactured by Bioject, allows delivery of Serostim/Saizen by subcutaneous injection through the skin in a fine stream in less than a second. SeroJet has been shown to be bioequivalent to needle injections.
Manufacture: Recombinant hGH is produced by a mammalian cell line (murine C-127) transformed with the hGH gene. Recombinant hGH with the correct three-dimensional configuration is secreted directly through the cell membrane into the cell-culture medium for collection and purification.
FDA class: Drug NDA
Approvals: Date = 19960823; first approval of Serostim, NDA; accelerated approval; orphan designation (granted 11/15/1991; expires 8/23/2003); Indication = for treatment of HIV-infection-related cachexia or wasting
Date = 19961008, NDA supplement; first approval of Saizen, NDA; Indication = for treatment of human growth hormone deficiency
Date = 20000626; NDA supplement; Indication = approval of the cool.click needle-free device for subcutaneous delivery of Saizen [first needle-free delivery system for hGH in the U.S.]
Date = 20010306; NDA supplement; Indication = approval of SeroJet needle-free device for injection of Serostim
Date = 20030829; NDA, accelerated approval for SeroStim; Indication = for treatment of HIV-related cachexia or wasting to increase lean body mass and body weight, and improve physical endurance.
Date = 20031202; NDA supplement; orphan designation (expires 12/2010); Indication = approval of Zorbtive, for short bowel syndrome
Date = 20040709; NDA supplement; Indication = approvals of an additional manufacturing facility, Farmaceutica Serono S.p.A. in Bari, Italy (IFS- Bari); a new delivery system consisting of a pre-assembled reconstitution device, ‘Click.easy’ which contains a vial of Saizen or Serostim and a cartridge of 0.3% (w/ v) metacresol in Water for Injection; and an auto-injector pen called the ‘One.click’ to be used exclusively with the Click.easy.
Date = 20041102; NDA supplement; Indication = approval for replacement of endogenous growth hormone in adults
Date = 20050211; NDA supplement; Indication = approval of SerStim LQ, a new liquid injectable formulation of SeroStim
Date = 20071108; NDA supplement; Indication = approval of easypod delivery system for the administration of Saizen
Indications: [full text of "INDICATIONS AND USAGE” section of Saizen product insert/labeling, 4/2005]
Pediatric Patients - Saizen [somatropin (rDNA origin) for injection] is indicated for the long-term treatment of children with growth failure due to inadequate secretion of endogenous growth hormone.
Adult Patients - Saizen is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria:
1. Adult Onset: Patients who have growth hormone deficiency either alone, or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
2. Childhood Onset: Patients who were growth hormone deficient during childhood who have growth hormone deficiency confirmed as an adult before replacement therapy with Saizen is started.
In both of these patient populations, growth hormone deficiency should be confirmed by an appropriate growth hormone stimulation test.
[full text of "INDICATIONS AND USAGE” section of Serostim product insert/labeling]:
Serostim [somatropin (rDNA origin) for injection] is indicated for the treatment of AIDS wasting or cachexia. This indication is based on analyses of surrogate endpoints in studies of up to 12 weeks in duration. Concomitant anti-viral therapy is necessary (see PRECAUTIONS: General). The continued use of Serostim treatment should be reevaluated in patients who continue to lose weight in the first two weeks of treatment.
[full text of "INDICATIONS AND USAGE” section of the Zorbtive product insert/labeling]:
Zorbtive [somatropin (rDNA origin) for injection] is indicated for the treatment of Short Bowel Syndrome in patients receiving specialized nutritional support. Zorbtive therapy should be used in conjunction with optimal management of Short Bowel Syndrome. specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for individual patient requirements and preferences. Nutritional supplements may be added according to the discretion of the treating physician. Optimal management of Short Bowel Syndrome may include dietary adjustments, enteral feedings, parenteral nutrition, fluid and micronutrient supplements, as needed.
Status: The Orange Book reports patent 5,898,030, "Pharmaceutical compositions containing hGH stabilized by means of saccharose. The formulation is particularly suitable for stabilizing a lyophilisate of recombinant hGH," expires April 27, 2016.
No centralized EU approval (country-by-country)
Due largely to restrictions of the Orphan Drug Act, i.e., other hGH products already approved with orphan drugs status, Serono was blocked from receiving approval entering the U.S. market with hGH until Oct. 8, 1996, when it received approval of Serostim for HIV/AIDS-related cachexia (wasting).
Saizen, was first introduced in Europe in 1989. As of July 2000, Saizen had been approved for growth hormone deficiency (75 countries), Turner Syndrome (58 countries) and chronic renal failure (18 countries).
Serostim received its initial accelerated approval for HIV/AIDS-related cachexia on Aug. 23, 1996, with a review time of ~11.4 months (~.95 year). 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. It was estimated that the time to approval was shortened by over 11 months by receipt of accelerated approval (vs. traditional, clinical endpoint-based, full approval). Approval was granted on the basis of improvements in surrogate, rather than clinical, endpoints, on the basis of two, 12-week, placebo-controlled, Phase III trials. Increase in total body weight was the primary surrogate marker for clinical efficacy. Upon approval, Serono pledged to conduct additional trials, including a study of patients’ physical condition as measured by treadmill performance.
In April 1999, the Health Care Finance Administration (HCFA; now Center for Medicare and Medicaid Services/CMS) mandated that all states provide Medicaid reimbursement of Serostim. The agency recognized the clinical utility of Serostim for AIDS-related wasting. This reversed a previous policy that Serostim could be considered a drug for cosmetic weight gain (which allowed states to refuse coverage).
On June 26, 2000, FDA approved a needle-free device (cool.click) to deliver Saizen, the first needle-free delivery system for growth hormone in the U.S. The cool.click device allows physicians and nurses to offer an alternative to patients other than traditional needles and syringes.
Counterfeit (fake; mislabeled) Serostim has been found in the U.S. market. In mid-2001, a counterfeit lot from an unknown source was found to contain 1 mg hGH (not 6 mg), of hGH definitely not manufactured by Serono.
In late 2002, Serono filed a supplemental NDA for approval of Serostim for treatment of short bowel syndrome in patients receiving specialized nutritional support, after obtaining orphan drug designation and positive results in a Phase III trial. In June 2003, FDA’s Gastrointestinal Drug Advisory Committee voted 6-3 to recommend against approval for this indication. This was largely attributed to nearly all patients having been treated at a single center and the 4-week trial presumed to be too short. Going against the review committee, on Dec. 2, 2003, FDA approved Zorbtive for short bowel syndrome with orphan drug designation, granting the product seven years of market exclusivity (protection against approval of a comparable/identical product with the same indication). Zorbtive was launched in the U.S on May 4, 2004.
In spring 2003, the CPMP, EMEA, European Union, recommended rejection of Serono’s application for approval of Serostim for treatment of AIDS-related cachexia, with this highlighting some of the differences between FDA and EU drug approvals. The CPMP found Serostim to have an unfavorable risk-benefit ratio and considered the target population too difficult to define, with HIV/AIDS patients concomitantly receiving varying combinations of antiretroviral and other drug regimens and having heterogeneous body compositions. At the time, Serono reported that this contradicted what the Committee on Orphan Medicinal Products (COMP), EMEA, had previously told the company - that trials should be in agreement with HIV/AIDS disease and patient definitions issued by the CDC in the U.S. Besides the same trials used to support FDA approval, Serono also submitted trial GF-9037, a U.S. post-marketing study in 766 patients showing increased exercise performance and lean body mass at 12 weeks. The CPMP also faulted the filing for lack of long-term controlled efficacy data, and expressed concerns about the long-term safety of repeated courses of Serostim in AIDS patients.
Trials with Serostim in AIDS patients ran from 1997-2002, a period during which antiretroviral combination therapies, including new HIV protease inhibitors, became available, with nearly all patients repeatedly switching combination drug regimens as new drugs were approved and as they developed resistance to drugs they have been taking. Serono asserted that their testing fully reflected the changes in HIV drug treatment and patient populations, with similar response rates observed across the full spectrum of patients.
In Jan. 2005, Serono launched Saizen in the U.S. for adult growth hormone deficiency. Patients who were growth hormone deficient during childhood and have growth hormone deficiency as an adult may continue to use Saizen as adults. It is also used by adult patients who have adult onset growth hormone deficiency either alone, or associated with multiple hormone deficiencies.
In 2nd quarter 2006, Serono filed a supplemental BLA for approval of Zorbtive for treatment of HIV-associated Adipose Redistribution Syndrome (HARS).
Tech. transfer: Novo Nordisk A/S holds a composition-of-matter patent, U.S. 5,633,352, covering aspects of recombinant human growth hormone. On October 6, 1997, Novo Nordisk filed a patent infringement lawsuit in the U.S. District Court for the District of New Jersey alleging that other recombinant hGH manufacturers – Genentech, Inc., Eli Lilly & Co., Pharmacia & Upjohn Co. (now Pfizer.) and Serono Laboratories, Inc. – infringe the patent. Novo Nordisk cited Saizen/Serostim as infringing its patent. In May 1998, Serono Laboratories, Inc. announced an out-of-court settlement with Novo Nordisk concerning the manufacture and marketing of Saizen and Serostim in the U.S., including Serono licensing U.S. 5,633,352 from Novo Nordisk. Financial and other terms were not disclosed. Novo Nordisk reports that this settlement had no significant impact on its financial results.
In August 2004, in a separate case, the U.S. District Court of Delaware ruled that Novo Nordisk A/S’ patent, 5,633,352, was invalid and unenforceable due to inequitable conduct. Savient Pharmaceuticals filed this suit in connection with its efforts to marketing of its hGH product, Tev-Tropin, in the U.S. Novo Nordisk appealed this decision, and subsequently cross-licensed its hGH patents with Savient. See the Tev-Tropin entry.
Ares-Serono has reportedly licensed recombinant mammalian cell culture technology from Celltech Biologics, now assigned to Lonza Biologics plc, a subsidiary of Alusuise-Lonza Group. Lonza also retains some unspecified manufacturing rights. Licensing likely involves the “Boss” patents covering use of the GS (glutamine synthetase) mammalian gene expression system. Related patents include U.S. 5,770,359 and 5,747,308. The technology is coa (see related entry), (see related entry),ssigned to the University of Glasgow (which presumably receives a share of royalties). The GS gene is used in recombinant vectors as a marker along with the gene(s) for the desired protein, with only successfully transformed cells capable of producing their own GS and surviving in glutamine-deficient culture media. Over 40 companies have licensed GS System technology for various uses.
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.
Disease: Short bowel syndrome (SBS) is a rare, serious and potentially life-threatening condition that follows extensive surgical removal of portions of the small intestine as a treatment for acute or chronic disorders of the intestine. The small intestine is an integral part of the digestive system, absorbing about 90% of the significant nutrients needed to sustain life. When less than half of the small intestine is removed, the body will generally compensate. However, when half or more is removed, the remaining portion simply cannot absorb sufficient electrolytes, water or necessary nutrients, resulting in SBS, for which Zorbtive is the only approved hGH product. Standard treatment for SBS involves careful management of dietary intake and hydration; or where needed, parenteral nutrition in which patients are fed liquid nutrients through an intravenous tube. Parenteral feeding can require being hooked up to an intravenous feeding line for 8-10 hours/day. On rare occasions, surgical transplant of the intestine may also be performed for treatment of SBS. Zorbtive can reduce dependence on parenteral nutrition for SBS.
There are an estimated 10,000-20,000 patients in the U.S. receiving intravenous parenteral nutrition for SBS, with these constituting the potential market for Zorbtive.
Trials: In a randomized double-blind, controlled, parallel group Phase III clinical study, Zorbtive administered with specialized nutritional support significantly reduced patient dependence on total parenteral nutrition as measured by total volume, total calories and frequency of infusion. Patients taking Zorbtive and a supplemented specialized diet reduced the average number of days they had to use intravenous nutrition by 4.2 days per week versus baseline, a significant reduction compared to the control group; and the proportion of patients who were able to completely discontinue intravenous feeding was greater among those who received Zorbtive. Results persisted at the 12-week post-treatment follow-up assessment.
In June 2004, Serono initiated a Phase III trial with Serostim to reduce excess visceral fat accumulation in patients with HIV-associated adipose redistribution syndrome (HARS). Serono has previously reported positive findings from the double-blind, placebo-controlled Treatment of Adipose Redistribution Syndrome (STARS) study.
In Jan. 2006, Serono reported the completion of its pivotal Phase III double-blind, placebo-controlled trial of Zorbtive in the treatment of HIV-associated adipose redistribution syndrome (HARS), an additional indication with orphan designation. This trial in over 300 patients studied whether daily administration of rhGH as treatment for the abnormal fat accumulation and distribution associated with HARS reduces visceral adipose tissue (VAT) more effectively than placebo. The trial met all primary and major secondary endpoints. In the first phase of the study, patients randomly received either rhGH 4 mg daily or placebo. rhGH was administered for 12 weeks and all patients were measured by CT scan to determine changes in VAT from baseline. In the second placebo-controlled phase of the study, rhGH was administered as 2 mg on alternate days for 24 weeks to assess the ability of a maintenance regimen to sustain improvements in VAT.
In Aug. 2006, positive results were reported from a pivotal Phase III 326-pateint trial of Zorbtive for the treatment of HIV-associated Adipose Redistribution Syndrome (HARS). This Phase III, double-blind, placebo-controlled study, was designed to evaluate Zorbtive as a for reducing abnormal accumulations of visceral fat. Patients receiving 4 mg daily for 12 weeks significantly reduced visceral adipose tissue (VAT), trunk fat, non-HDL cholesterol, and improved pre-specified health-related quality of life outcomes. Maintenance therapy for 24 weeks with a lower dose of rhGH helped sustain the clinical benefits. The study met all pre-specified primary and major secondary efficacy endpoints.
Medical: The recommended dosage of Saizen for children is 0.06 mg/kg (about 0.18 IU/kg) administered either subcutaneously or intramuscularly three times weekly. However, the dosage and schedule are generally customized for each patient. For adult growth hormone deficient patients, the recommended dosage at the start of therapy is not more than 0.005 mg/kg/day, which may be increased to not more than 0.01 mg/kg/day after 4 weeks depending upon patient tolerance of treatment. In addition to adverse effects, determination of age- and gender-adjusted serum IGF-I levels and clinical response (e.g., body composition assessments) may be used to help guide dose titration.
The recommended dosage of Serostim for a 45-55 kg adult is 5 mg subcutaneously daily (and 6 mg and 4 mg, respectively, for those above 55 kg and 35-45 kg) at bedtime. A course of treatment lasts two weeks (14 doses).
The recommended dose of Zorbtive is 0.1 mg/kg daily up by subcutaneous injection up to a maximum of 8 mg/day for a treatment period of four weeks.
Acting as an anabolic (protein building) and anticatabolic (protein sparing or protecting) agent, Serostim therapy results in a significant increase in lean body mass and weight, with a decrease in body fat. Preventing the continued loss of lean body mass, as well as promoting the accrual of lean body mass, are keys to improving quality of life and physical function in AIDS patients with cachexia (wasting). Serostim does result in an increase in HIV replication, plasma viral load, or exacerbate other HIV/AIDS-related symptoms.
Market: In 2009, Saizen was reported to have 9% market share and Serostim 3% market share of the worldwide $2.75-$3.0 billion hGH market, indicating annual revene of <$30 million for Saizen and <$9 million for Serostim. Zorbtive is an even smaller market.
Total recombinant hGH (Saizen, Serostim and Zorbtive) sales by Serono have been reported to be $298 million in 2011; $311 million in 2010; $260 million in 2009; $220 million in 2008; $208 million in 2007; $275.7 million in 2006; $276.9 million in 2005; $269.8 million in 2004; $240.2 million in 2003; $219.1 million in 2002; and 228.1 million in 1999.
Total sales of Saizen were $206.5 million in 2005; $182.1 million in 2004; $151.5 million in 2003; $124.0 million in 2002, and $107.3 million in 2001; $90.7 million in 1999, and $88.8 million in 1998.
Total sales of Serostim were 70.4 million in 2005; $86.8 million in 2004; $88.8 million in 2003; $95.1 million in 2002, and $125.3 million in 2001; $137.4 million in 1999, and $88.2 million in 1998. The decrease in Serostim sales in 2005 is attributed by Serono to a charge to pay for the settlement of a U.S. government investigation into marketing practices of AIDS-wasting drug Serostim.
Serono’s investment in needle-free Saizon has been attributed as
Boosting related revenues from $2 to $60 million in 4 years.
Sales of Zorbtive were $54 million in the first three quarters of 2005, indicating 2005 sales of ~$72 million.
Serono has projected peak Zorbtive sales of $15-20 million annually for short bowel syndrome.
The 2007 Average Wholesale Price (AWP) for Saizen is $476.80/8.8 mg vial, and $4298.00/5 mg vial (Red Book, 2007). The 2007 AWP for Saizen Click Easy Cartride is $476.80/8.8 mg cartridge, and $2,383.98 for five.
The 2007 AWP for Serostim is $1,302.72 for seven 4 mg vials; $1,648.20 for seven 5 mg vials; and $1,954.08 for seven 6 mg vials (Red Book, 2007).
The 2007 AWP for Zorbtive is $5,376.00 for seven 8.8 mg vials (Red Book, 2007), unchanged from 2005.
In Dec. 2005, Serono reached a settlement with the U.S. Department of Justice related to allegations of improper marketing of Serostim, including kick-backs to physicians. The company paid $705 million ($137 million criminal fine and $567 million in civil penalties) to cover potential fines/penalties and other settlement costs. This only involved the federal government’s claims and interests in reimbursement. This expense was the primary cause of Serono reporting a loss in 2005, in contrast with recent prior years. Among other activities, Serono sales executives had offered physician all-expenses paid trips to a medical conference in Cannes, France. In return, the physician would write at least 10 additional prescriptions in one week for a 12-week treatment course of Serostim. Serono also plead guilty to charges that, between Sept. 1996 and Jan. 2002, it conspired with a medical device manufacturer (RJL Systems Inc.) to market an unapproved software test package used to diagnose AIDS wasting, which resulted in inflated demand for Serostim, which in turn caused Medicaid to overpay for its purchase.
In March 2006, a U.S. class action lawsuit was filed regarding the Serono’s marketing methods to promote Serostim, including for unapproved uses and improper use of the RJL Systems AIDS wasting diagnostic. It was filed on behalf of the Government Employees Hospital Association, the third-largest national health insurance plan in the U.S., and a New York-based union. This filing amended for a second time a class action lawsuit first filed in Sept. 2005 and first amended in Nov. 2005 to include allegations that Serono illegally promoted and marketed Serostim. The initial complaint had only alleged inflated wholesale prices. In Feb. 2007, this suit was settled with Serono paying $24 million to be divided among health plans, insurers and individuals having purchased Serostim.
Ongoing: Merck Serono is developing ARX201 using ReCODE technology from Ambrx. ARX201 involves a hGH mutein with a amino acid substitution to which a polyethylene glycol (PEG) polymer strand is attached. The confers enhanced potency, reduced dosing frequency, improved product homogeneity and facilitates manufacturing, besides offering a strong intellectual property position.
For Merck Serono, Nautilus Biotech S.A. has been developing a next-generation hGH with point mutations designed to prevent degradation by proteases and an improved pharmacological profile (less frequent injections).
Companies involvement:
Full monograph
257 Somatropin, rDNA/MerckSerono
Nomenclature:
Somatropin, rDNA/Merck Serono [BIO]
Saizen [TR for hGH deficiency]
Serostim [for AIDS-related cachexia]
Zorbtive [TR for short bowel syndrome]
Click.easy [TR for reconstitution device]
cool.click [TR for injector]
One.click [TR for injector]
Somatropin (rDNA origin) for injection [FDA]
somatropin (human) [CAS]
12629-01-5 [CAS RN]
hGH [SY]
human growth hormone, recombinant [SY]
rhGH [SY]
somatomammotropin [SY]
NDC 44087-1005-2 for Saizen; NDC 44087-0004-7; NDC 44087-0005-7; NDC 44087-0006-7 for Serostim [NDC]
NDC 44087-1006-1 and NDC 44087-1006-7 [NDC]
molecular weight (kDa) = 22
FDA Class: Drug NDA
Year of approval (FDA) = 1996
Date of 1st FDA approval = 19961008
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2016; Orange Book reports patent 5,898,030, expiring on April 27, 2016. |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 2008 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2003 |
U.S. Biosimilars Launchability Year: | 2016 |
U.S. Biobetters Launchability Year: | 2016 |
Biosimilars/biobetters-related EU Patents: | equivalents of PCT/IT94/00086 apparently expired in/by 2004 |
EU Patent Expiration Year: | 2011 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2004 |
EU Biobetters Launchability Year: | 2004 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth hormones
hormones
murine (mouse) materials used
recombinant DNA
C-127 (C127) murine tumor cells
glutamine synthetase (GS) expression system
mammalian cell culture
murine tumor cells C-127 (C127)
rodent cells <!-- rodentcells -->
Bacteriostatic Water for Injection
benzyl alcohol
citric acid
lyophilized (freeze-dried)
phosphoric acid
poliovirus type 3
sodium hydroxide
Sterile Water for Injection
Sterile Water for Injection
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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