Tercica
Mecasermin recombinant - Increlex; IGF-1
Status: approved and EU
Organizations involved:
Tercica, Inc. – R&D; Tech.
Ipsen S.A. – Intl. mark.; World mark.; Parent
Cambrex Bio Science Baltimore – Manuf.
Lonza Biologics plc – Parent
Cambrex Bio Science, Inc. – Parent; Former
Baxter Pharm. Solutions LLC – Manuf. other
Genentech Inc. – R&D; Tech.; Former
Astellas Pharma Inc. – Japan mark.
Biologix FZ Co. – Mid. East/Africa mark.
Giddi Pharma Co. – China (Taiwan) mark.
Fujisawa Pharmaceuticals, Inc., Ltd. – Former
Cross ref.: See the entries in this section for the other insulin-like growth factor products.
Description: Increlex is an aqueous formulation of recombinant nonglycosylated human insulin-like growth factor-1 (IGF-1) protein expressed by Escherichia coli (E. coli) bacteria. This 70 amino acid protein is in the form of in a single chain with three intramolecular disulfide bridges; has a molecular mass of 7.649 kDa; a molecular formula of C331H512N94O101S7. The molecule is substantially similar to human IGF-1 that must be present in human tissues for normal growth and metabolism.
Increlex is packaged in multi-dose 5 mL glass vials as a sterile, aqueous, clear and colorless 4 mL solution intended for subcutaneous injection. Each vial contains 10 mg/mL mecasermin recombinant (40 mg total), 9 mg/mL benzyl alcohol, 5.84 mg/mL sodium chloride, 2 mg/mL polysorbate 20, and 0.05M acetate at a pH of approximately 5.4. Increlex is stored at 2-8ºC (refrigerated). For its manufacture, no excipients of either are animal or human origin are used.
Nomenclature: Insulin-like Growth Factor-1, rDNA/Tercica [BIO]; Increlex [TR]; mecasermin recombinant [FDA]; mecasermin [USAN INN BAN]; insulin-like growth factor I (human) [CAS]; 68562-41-4 [CAS RN]; 67763-96-6 [CAS RN; from NLM]; rhIGF-1 [SY]; CEP-151 [SY]; CEP 151 [SY]; somatomedin C [SY]; somazon [SY]; NDC-15054-1040-5 [NDC}
Biological.: Human IGF-1 is a hormone involved in growth and metabolism. IGF-1 production is triggered by human growth hormone (hGH), which is secreted by the pituitary gland. IGF-1 and hGH are both required for normal growth in children. Insufficient blood levels of either IGF-1 or hGH during childhood result in short stature. For more than 40 years, children with short stature caused by hGH deficiency have been treated with replacement growth hormone therapy [see the Somatropin (hGH) Products entry]. In these cases of hGH deficiency, therapy with GH stimulates IGF-1 production and the children grow. However, children with primary IGF-1 deficiency (IGFD) or growth hormone insensitivity syndrome (GHIS; Laron Syndrome), despite normal levels of hGH, have low levels of IGF-1. Affected individuals have severe short stature and very low levels of IGF-I and/or IGF binding protein-3 (IGFBP-3), which do not increase in response to exogenous growth hormone (somatropin) administration. These children are not responsive to their own hGH, nor is it likely that they will respond to hGH treatment. These children often can grow when treated with IGF-1 (or IGF-1/IGFBP-3).
Companies.: IGF-1 was originally developed by Genentech, Inc. Dr. Ross Clark left Genentech’s IGF-1 development team and founded Tercica in New Zealand in 2000, concentrating on IGF-1 for treatment of short stature. Tercica later relocated to the U.S., and completed its initial public offering (IPO) in 2004.
Tercica (now merged into Ipsen S.A.) entered into a U.S. license and collaboration agreement regarding Increlex with Genentech in April 2002, which was amended in July and Nov. 2003. In July 2003, Tercica’s rights were expanded to the remaining territories of the world outside of the U.S. Under these agreements, Tercica has rights and licenses to Genentech’s intellectual property to research, develop, use, manufacture and market recombinant IGF-1, alone or in combination with IGFBP-3 for a broad range of indications:. Genentech has the option to jointly commercialize IGF-1 for all diabetes and non-orphan indications: in the U.S. GenenTech. transferred its preclinical and clinical data related to IGF-1. This included results from extensive animal testing as well as Phase I, Phase II and Phase III clinical trials with IGF-1. Insmed’s rights are exclusive for development and sale of IGF-1 and nonexclusive for manufacture of IGF-1. indications: not covered by the company’s licenses from Genentech include diseases and conditions of the central nervous system. Tercica must enter into a written agreement with another unspecified company if its desires to commercialize IGF-1 for diabetes outside of the U.S.
Upon agreement execution, Tercica paid Genentech $1.0 million in cash and ~$4.1 million in stock. Another $1.7 million was paid upon execution of the international agreement. Genentech received $1.3 million for license to its rights to IGF-1 combined with IGFBP-3. Insmed also will pay Genentech unspecified royalties on the sales of IGF-1 products and certain one-time milestone events. If Insmed achieves all of its development milestones, Genentech will receive up to ~$66.5 million. If Insmed discontinues development of rhIGF-1 products for diabetes or a substitute indication it selects (subject to Genentech’s consent), Genentech has the right to assume development for this indication and would receive licenses to patents held by Tercica. Any substitute indication agreed to be Genentech must have a potential market >$250 million and not be an indication for the central nervous system.
In Dec. 2002, Tercica entered into a development and commercial supply contract with Cambrex Bio Science Baltimore, Inc., then a subsidiary of Cambrex Bio Science, Inc., for the manufacture of bulk IGF-1 drug substance. Lonza Biologics plc acquired the contract manufacturing subsidiary of Cambrex in mid-2006. Cambrex was originally contracted to manufacture bulk rhIGF-1 through Dec. 2008, and was obligated to provide up to 24 kilograms of rhIGF-1 per year. Tercica had reported that its total purchase commitment to Cambrex was ~$8.5 million through Dec. 31, 2005 (reflecting scaleup and purchases for clinical trials).
In April 2013, Tercica reported "manufacturing issues with Increlex at its Hopkinton site (MA)," indicating API manufacture at this site, with shortages expected in coming months and more supply available later in the year. Ipsen had been battling to keep a steady supply of the drug for more than a year-and-half after the FDA in a 2011 warning letter questioned whether Lonza could stand behind the potency and purity of APIs being manufactured at the Hopkinton facility. FDA had reported that "Current lots of Increlex in the marketplace
were manufactured using an alternative drug substance manufacturing facility that has not been approved by the
FDA." Apparently, the transfer of manufacture to Lonza's Hopkington, MA, facility and/or release of product from this facility had not been fully FDA-approved; and it was reported the Ipsen would seek FDA approval for manufacturing the Hopkinton site.
In April 2013, a shortage of Increlex developed after FDA effectively halted manufacture.
Formulation, fill and finishing services are reported to be provided by Baxter Pharmaceutical Solutions LLC, a subsidiary of Baxter Healthcare.
Fujisawa Pharmaceuticals, Inc., Ltd. partnered with Tercica for IGF-1 development in Japan for treatment of insulin resistance. Fujisawa licensed patents concerning IGF-1 and diabetes to Tercica in April 2004. In spring 2005, Fujisawa completed its merger with Yamanouchi Pharmaceutical Co. Ltd.. forming Astellas Pharma Inc.
In June 2006, Tercica concluded agreements with with Biologix FZ Co. and Giddi Pharma Co. Biologix received exclusive marketing rights in 17 Middle East and North African countries. Giddi received exclusive marketing rights in Taiwan.
In July 2006, Tercica concluded an agreement with Ipsen S.A., Tercica granted Ipsen exclusive rights to market Increlex for the treatment of short stature associated with severe primary IGF-1 deficiency (primary IGFD) in all regions of the world except the U.S., Japan, Canada, the Middle East and Taiwan. Tercica recieves a tiered royalty from Ipsen ranging from 15%-25%, in addition to a supply price of 20% of net sales. Ipsen made an upfront cash payment of ~$12.5 million to Tercica, and will pay an additional ~$18.8 million on approval of the Increlex in the European Union. Ipsen acquired an initial 25% stake in Tercica, with the potential to increase this to 40% ownership. The companies granted each other development rights and will share the costs for improvements to or new indications: for Increlex.
In July 2007, Genentech and Tercica formed a collaboration for development of two combination products containing Genentech’s recombinant human growth hormone Nutropin AQ (somatropin; human growth hormone; see related entry) and Increlex from Tercica for the treatment of growth hormones-related disorders. Nutropin AQ and Increlex were both originally designed and formulated so that they potentially could be combined and given as a single, daily injection. One combination product will be for patients with low IGF-1 levels and short stature not associated with growth hormone deficiency; and the second combination product will be for patients with AGHD. Tercica is eligible for up to $53 million in equity payments, opt-in payments, R&D cost reimbursement, and milestone payments; and Genentech purchased 708,591 shares of Tercica’s common stock for $4 million. Tercica will fund and lead initial development efforts for both products. Genentech has certain rights to opt-in to the development programs. with these open until completion of a Phase II clinical study for each product that is sufficient to enable a pivotal trial. If Genentech does not exercise any of its opt-in rights, Tercica will have full rights to the combination products, and will pay Genentech royalties on worldwide sales.
In June 2008, Ipsen fully acquired Tercica for ~ $663 million. Ipsen had already owned slightly over 25% of Tercica stock.
Manufacture: In 2004, Cambrex (now Lonza) completed its Increlex manufacturing conformance lot campaign and successfully validated the Increlex cGMP manufacturing process. This included transfer of proprietary high yield manufacturing technology from Genentech. Cambrex-manufactured IGF-1 used in Tercica’s pivotal Phase III trial.
Based on extensive testing, Tercica believes that Increlex is comparable to the rhIGF-1 previously manufactured by Genentech. Differences between the production of the Genentech-manufactured rhIGF-1 and Increlex include relocation of manufacturing to Baltimore, Inc.; use of a new Master Cell Bank (MCB) derived from Genentech’s MCB; change of some of the raw material suppliers; change of the final vial size and configuration; unspecified process changes; analytical methods changes; in equipment used; and change in the solvent used in the purification process.
The Genentech/Tercica/Cambrex method for manufacture of IGF-1 is probably similar to that described for IGF-1 in the iPlex (IGF-1/IGFBP-3) entry.
FDA class: Drug NDA
Approvals: Date = 20050830; original approval (NDA 21-839); orphan drug; Indication = pediatric treatment of growth failure
Date = 20120612; BLA supplement; Indication = labeling change; addition of ‘Skin and Subcutaneous Tissue Disorders: alopecia, hair texture abnormal’ to section 6.3, the Post-Marketing Experience subsection of the Adverse Reactions section of the Package Insert (PI)
Date = 20110216; BLA supplement; Indication = conversion of the package insert into the Physician Labeling Rule (PLR) format, and labeling has been revised to include information on systemic hypersensitivity reactions,
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
Increlex (mecasermin [rDNA origin] injection) is indicated for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Severe Primary IGFD is defined by: height standard deviation score ≤3.0 and basal IGF-1 standard deviation score ≤3.0 and normal or elevated growth hormone (GH).
Severe Primary IGFD includes patients with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.
Increlex is not intended for use in subjects with secondary forms of IGF-1 deficiency, Such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Increlex treatment.
Increlex is not a substitute for GH treatment.
Status: On Feb. 28, 2005, Tercica submitted an NDA in the electronic Common Technical Document (eCTD) format seeking approval of Increlex for long term treatment of growth failure (short stature) with orphan designation in children with severe primary IGF-1 deficiency (Primary IGFD). The NDA filing was accepted on May 2, 2005 for priority review with a PDUFA of Aug. 31, 2005.
The NDA was approved on Aug. 30, 2005. Increlex became the first alternative to somatropin (human growth hormone) products for treatment of short stature. FDA also separately granted orphan drug status for primary IGF-1 deficiency. Increlex had originally been granted orphan drug status for growth hormone insensitivity syndrome (GHIS), but Tercica filed an amendment to change this to define the patient population “more accurately.”
Several weeks before the approval of Increlex, Insmed Inc. (marketer of iPlex) filed a Citizen Petition with FDA seeking FDA to deny approval of Increlex. Insmed alleged that “Tercica’s NDA does not include data that adequately ascertain and document the risk of hypoglycemia and other serious adverse events” associated with IGF-1; and that studies of the the safety and efficacy of Increlex were largely based on a retrospective analysis of data collected from a compassionate use program with IGF-I in GHIS, with these programs generally underestimating adverse events.
On Jan. 3, 2006, Tercica launched Increlex in the U.S. Tercica was then conducting a Phase III trial using once-daily dosing, and expected to file a NDA supplement for non-severe primary short stature in 2007-2008 (see the Trials section below).
On Dec. 7, 2006, Tercica filed a MAA application in the European Union application for the long-term treatment of growth failure in children with severe primary IGF- deficiency (primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. On Aug. 8, 2007, EU approval was granted with orphan designation (10 years market exclusivity). Ipsen markets Increlex in Europe.
In May 2013, problems with manufacture by Lonza were reported, with this expected to lead to shortages, with these potentiay severe starting in 3rd-quarter 2013.
Tech. transfer:
As discussed above in the Companies section, in 2002 Genentech granted Tercica an exclusive license for IGF-1, including manufacturing methods. This includes U.S. 6,331,414, “Preparation of human IGF via recombinant DNA technology,” Dec. 18, 2001, expiring Dec 18, 2018, assigned to Genentech. This patent claims recombinant constructs and methods for E. coli manufacture of IGF-1. In 2004, Tercica recorded $1.4 million as an acquired in-process research and development expense related to the license of certain rights to IGF-1 and IGF-1/IGFBP-3. This patent expires in 2018. There is no equivalent European patent. The European Patent Office (EPO) has determined that the claims of Genentech’s patent application were not patentable in view of public disclosures made before the application was filed.
On Dec. 20, 2004, Tercica and Genentech initiated patent infringement proceedings against Insmed Inc. and Avecia Ltd. (the developer and manufacturer, respectively, of IGF-1/IGFBP-3 or IPlex; see related entry) as codefendants in the U.K. High Court of Justice (Chancery Division Patents Court). Tercica and Genentech allege that manufacture of IPlex by Avecia and its commercialization infringes European Patent No. 0 571 417 assigned to Genentech and licensed to Tercica concerning combining IGF-1 and IGFBP-3 for the treatment of short stature. In May 2005, the U.K.’s High Court of Justice will begin deliberating the patent infringement suit.
On Dec. 23, 2004, Tercica and Genentech initiated patent infringement proceedings against Insmed Inc. in the U.S. District Court for the Northern District of California. The companies allege that manufacture, use, and commercialization of IPlex for the treatment of growth hormone insensitivity syndrome (GHIS) infringe and/or will infringe U.S. 5,187,151 and 6,331,414, assigned to Genentech and exclusively licensed to Tercica. These patents include claims for the combination/complex of IGF-1 and IGFBP-3. This was amended on Feb. 16, 2005 to include infringement of an additional patent. On Feb. 22, 2005, Insmed filed a motion to dismiss the lawsuit claiming statutory safe harbor provided by 35 U.S.C. ss. 271(e)(1), [Clinical Trial Exemption] that prevents finding of patent infringement against a product while it is being tested in clinical trials, that the filings were an attempt to delay IPlex’s NDA, lack of an inventive step in these patents, and other reasons. In April 2005, the U.S. District Court for the Northern District of California granted Insmed’s motion to dismiss the suit against Tercica and Genentech, but also granted 30 days for the companies to file an amended suit.
Fujisawa Pharmaceuticals, Inc., Ltd. has obtained various patents concerning IGF-1 and diabetes, and licensed these to Tercica in April 2004. In spring 2005, Fujisawa completed its merger with Yamanouchi Pharmaceutical Co. Ltd.. forming Astellas Pharma Inc.
Tercica (and Genentech) apparently lack composition-of-matter, e.g., gene/protein sequence, patent protection for IGF-1, which is apparently in the public domain.
Cephalon, Inc. has received U.S. 6,207.806, “IGF-1 Purification Process,” claiming substitution of reverse phase chromatography for gel filtration chromatography in the purification of IGF-1, with a three-fold increase in yield. The use/nonuse of this invention (and licensing) has not been disclosed.
Trials: The NDA filing was based on a pivotal Phase III trial of IGF-1 for the treatment of short stature caused by Severe Primary IGF-1 deficiency (IGFD; GHIS). Results from the study, presented in June 2004, showed a statistically significant increase (p < 0.001) in growth rate over an eight-year period in response to IGF-1 therapy. Compared to pretreatment growth patterns, on average, children gained an additional inch per year for each year of therapy over the course of eight years. An analysis of safety in the study concluded that long-term treatment with rhIGF-1 appears to be well tolerated and has an acceptable safety profile. The most common adverse events were hypoglycemia, lipohypertrophy and tonsillar hypertrophy. No patients withdrew from the study due to side effects. This trial enrolled 71 children with Severe Primary IGFD with rhIGF-1 replacement therapy for an average of 3.9 years, with some patients being treated for up to 11.5 years. Of these children, 61 completed at least one year of rhIGF-1 replacement therapy, which is the generally accepted minimum length of time required to adequately measure growth responses. Baseline characteristics of the patients included a height range of 28.6 to 41.2 inches and an age range of 2-10 years. A statistically significant increase in average growth rate—from 2.8 cm per year prior to treatment to 8.0 cm per year after the first year of rhIGF-1 treatment—was demonstrated in these patients (p < 0.0001). Statistically significant increases in Height SDS were also observed during each of the first eight years of rhIGF-1 treatment (p < 0.001). Compared to pretreatment growth rates, statistically significant increases were also observed during each of the next five years of rhIGF-1 treatment (p < 0.005). The trial demonstrated that long-term treatment with rhIGF-1 resulted, on average, in a three-fold increase in the rate of growth in the first year of therapy, and a two-fold increase in growth rate over an eight-year period. These increases in growth rates are comparable to those observed in clinical trials of approved human growth hormone (somatropin) treatments. Hypoglycemia (low blood sugar) was the most common treatment-related adverse event, which was managed by eating at the time each dose was administered.
In July 2005, Tercica reported results from two pharmacokinetic studies showing that Increlex induced a prompt increase of insulin-like growth factor binding protein-3 (IGFBP-3) in the body. This is important because IGFBP-3 bind to IGF-1 (as with iPlex) and extends its circulating time in the blood. Increlex induced an average 32% increase in IGFBP-3 levels. The effects of Increlex on IGFBP-3 were consistent in severe and moderate IGF-deficient, as well as IGF-1-sufficient patients.
A randomized multicenter Phase IIIb trial began in Oct. 2004 in 160 children with a less severe form of Primary IGFD. The study is assessing the safety and efficacy of rhIGF-1 in promoting structural growth. Approximately 160 pre-pubertal children with a diagnosis of less severe primary IGFD will be enrolled in this study. The primary endpoint of this trial is the change in height standard deviation score over a one-year period of time. It is anticipated that the study will take two years to complete.
In Sept. 2005, results from a a study in 18 patients showed that once-daily dosing of Increlex was comparable to the approved twice-daily dosing regimen. At 24-hours, mean serum IGF-1 levels correlated to dose and IGFBP-3 (both p <0.01) but not to the schedules (p=0.38). Patients received subcutaneous 40 or 80 µg/kg twice-daily or 80 µg/kg once-daily for 3 weeks. If approved for once-daily dosing, this would increase the marketability and acceptance of Increlex vs. iPlex, and reduce the cost of its use (and total sales potential).
Tercica plans to initiate Phase II studies to evaluate Increlex’s efficacy and safety in type A and severe insulin-resistant type II diabetes. Data from a Phase II study presented in Sept. 2004 showed that Increlex in combination with glyburide improved HbA1c in type II diabetes.
In 2007, ongoing trials include the MS-301 study in non-severe IGFD patients and the MS-308 Phase III study of once-daily injection of Increlex. MS-301 began in Nov. 2005. In March 2007, the trial was 80% enrolled (109 of the 136 patients), with enrollment expected to be complete in mid-2007, data available by mid-2008, and FDA approval projected for late 2009. While all data will be submitted to FDA, the filing is expected to be based on one-year data. MS-308 is an open-label trial expected to enroll 45 children with less-severe IGFD (height of greater than two standard deviations below the mean height for the child’s age range). The primary endpoint of the study is change in height velocity at 34 weeks of treatment. Tercica expects full enrollment by mid 2007, and report data by mid-2008.
Medical: Increlex is administered to children as twice-daily injections at doses of 80-120 µg/kg body weight.
IGF-1 is widely considered to be more difficult to administer and more toxic than somatropin (hGH). Adverse effects include pseudotumor cerebri, with increased IGF-1 in the cerebrospinal fluid leading to increased fluid pressure on the brain; lymphoid hyperplasia, involving uncontrolled growth of lymphoid tissue; and coarsening of facial features (common in growth hormone insensitivity syndrome (GHIS)/Laron’s syndrome patients).
Disease: Patients with primary IGF-1 deficiency (primary IGFD) present with extreme short stature (height standard deviation score, SDS < -3) and an extremely poor prognosis for adult stature. Whereas prepubertal height SDS can range as low as -9, a blunted pubertal growth spurt is usually apparent, resulting in adult height that is typically 5-12 SD’s below the normal population (adult height between 100 and 140 cm). Profound short stature in patients is often associated with severe psychosocial problems.
There are an estimated 24,000 children in the U.S. with non-severe primary IGFD. The initial targeted market for treatment is the ~6,000 children in the U.S. with severe primary IGFD. Tercica believes the EU has ~30,000 children affected by primary IGFD, including ~6,000 children affected by severe primary IGFD, making the EU market for Increlex similar in size to the U.S.
Market: Increlex treatment, upon approval, had been reported to typically costs about $23,000/year. However, more recently, e.g., March 2007, the average cost is commonly cited as $14,000/year. This assumes an average 90 µg dose twice daily and a 70% compliance rate. Upon U.S. launch, Tercica had 15 field sales reps (while Insmed had yet to establish a sales team). This and the earlier of approval of Increlex gave it an initial advantage in marketing.
The 2007 Average Wholesale Price (AWP) is $6,210.00/ten 4 mL vials (Red Book, 2007).
Total product revenue was $36.8 million in 2012; ~$33 million in 2011; ~$40 million in 2010; $28.5 million in 2009; $6.6 million in 2008; $9.6 million in 2007 and; $1.3 million in 2006.
Regarding 2007 Increlex sales, Tercica had originally issued guidance for sales of $7-$8 million. This assumed roughly 550-600 patients with full reimbursement receiving treatment (up from 200 patients on the drug at the end of 2006); annual treatment cost of $14,000; iPLEX patients switch to Increlex; that many non-severe short-stature patients start Increlex before approval (off-label); and positive results from a trial in non-severe IGFD patients.
Tercica has estimated the non-severe IGFD market to be five times the size of the severe IGFD market (current approved indication).
Analysts’ projections of Increlex sales vary greatly.
In March 2007, after Increlex’s competitor, iPLEX, was removed as a competitor due to patent infringement (see the Tech. transfer section of the iPLEX entry below), analysts with Friedman Billings and Ramsey (FBR) projected Increlex sales of $8 million in 2007, $21 million in 2008, $44 million in 2009, and $69 million in 2010. If the ongoing Phase III trial in non-severe primary IGFD patients is successful, FBR expects this market to grow significantly, with a market potential of nearly $400 million in the U.S. alone. FBR presumed that the cost of Increlex treatment of severe IGFD will be about $20,000 or more per year, similar to the annual cost of somatropin products. There will likely be some off-label for non-severe disease prior to approval for this indication (expected to impact sales in 2009). FBR expects that initial penetration will be strong in its approved indication of severe primary IGFD, with modest off-label use in non-severe primary IGFD, with a European approval in severe primary IGFD in 2007. For 2007, FBR projects U.S. prevalence of primary IGFD at 30,603 patients, 18%/5,631 with severe disease, with 6% Increlex market penetration, an average number of 338 treated patients, U.S. sales in severe IGFD at $5 million; that 82% of patients or 24,972 have non-severe disease, with 1% (250 patients) market penetration, each spending an average of $9,800/year for treatment, with total U.S. sales for non-severe IGFD or ~$2 million; bringing total 2007 U.S. sales to ~7 million. Outside of the U.S., FBR projects prevalence of primary IGFD at 30,603 patients (same as U.S.), with 18% having severe disease, with market penetration of 1% (30 patients), an average cost of $12,600/patient/year, zero sales for severe IGFD, with total ex-U.S. sales of about $400,000. Total 2007 worldwide sales are projected to be ~$8 million.
Lehman Brothers has estimated a peak U.S. market for IGF-1 comparable to that for hGH (somatropin), about $550 million,
Many analysts’ presumptions regarding the potential market for Increlex are based on a study by Genentech and Tercica that estimated that there are ~6,000 patients with severe primary IGFD.
In June 2006, Tercica filed false advertising claims in federal court against Insmed regarding its marketing of iPLEX. Insmed then filed a countersuit alleging false advertising claims by Tercica. These disputes were resolved in March 2007 as part of Tercica winning its patent dispute with Insmed, with Insmed essentially removing iPLEX from the market (for its approved indication).
Competition: Increlex (IGF-1) and iPlex (IGF-1/IGFBP-3) compete against each other for the same approved indications:. However, Increlex is administered as a pen injection, which may be preferred by patients over the more conventional iPlex injection.
With over 40 years of experience using somatropin (hGH) products, the only currently approved products for treatment of short stature, it may be difficult to convince pediatric endocrinologists and other short stature-treating physicians to prescribe IGF-1 products. Somatropin (hGH) products approved for pediatric use are: Humatrope (Eli Lilly & Co.); Nutropin (Genentech); Norditropin (Novo Nordisk); Genotropin (Pfizer); and Saizen (Merck Serono). Tercica will have to get physicians to think of short stature in terms of IGF-1, rather than hGH, deficiency. Physicians will have to learn that short stature may be due to either insulin-like growth factor deficiency (IGFD; GHIS) leading to Laron’s syndrome; growth hormone resistance; or somatropin (hGH) deficiency; and new diagnostic methods will need to be adopted to differentiate among these causes of short stature.
With difficulties in diagnosis and the boundaries between the various causes of short stature difficult to determine, IGF-1 will compete against hGH products for patients with indeterminate diagnosis. hGH is currently indicated for use in children with inadequate levels of hGH, but FDA has not defined these levels (leaving this to the physician), although some insurers do set criteria. Current diagnostic tests include the IGF-1 generation test, with patients receiving hGH and then tested for IGF-1 levels 4-7 days later. If hGH increases IGF-1, the patient is expected to benefit from starting or continuing hGH. Otherwise, the patient is a candidate for IGF-1 products.
Skeptics of IGF-1 (Increlex) vs. IGF-1/IGFBP-3 (iPlex) may assert that its utility is questionable, due to many patients lacking IGFBP-3 required to form a 1:1 conjugate with IGF-1 (the active form in vivo; see the IPlex entry). Also, the number and characteristics of children with short stature who would best benefit from hGH vs. IGF-1 vs. IGF-1/IGFBP-3 remains to be determined.
Increlex competes against well-established somatropin (hGH) products for treatment of severe pediatric short stature. This is likely a major reason why Genentech, which developed and markets Nutropin (recombinant somatropin), which is highly profitable, outlicensed the product to Tercica. The main reason claimed/cited at the time was Genentech’s decision to concentrate its R&D on immunology, oncology and neurology. Earlier failure of IGF-1 (Myotrophin) from Cephalon and Chiron to gain approval also likely contributed to Genentech’s decision.
Ongoing: Tercica and Genentech are collaborating on development of a product that essentially combines Increlex plus Nutropin AQ, recombinant human growth hormone from Genentech. Phase II trials began in Jan. 2008.
In Nov. 2007, Celera Genomics and Ipsen entered into a research collaboration to develop biomarker and pharmacogenomic tests for growth failure patients.
Companies involvement:
Full monograph
201 Insulin-like Growth Factor-1, rDNA/
Nomenclature:
Insulin-like Growth Factor-1, rDNA/Tercica [BIO]
Increlex [TR]
mecasermin [USAN INN BAN]
insulin-like growth factor I (human) [CAS]
67763-96-6 [CAS RN; from NLM]
68562-41-4 [CAS RN]
CEP 151 [SY]
CEP-151 [SY]
rhIGF-1 [SY]
somatomedin C [SY]
somatomedin-1 [SY]
somazon [SY]
molecular weight (kDa) = 7.7 [70 a.a. polypeptide]
FDA Class: NDA
Year of approval (FDA) = 2005
Date of 1st FDA approval = 20050831
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2017 based on 5,681,814, the latest expiration cited in the Orange Book; 2019, based on extension of 5,681,818; 2019, based on extension of 5,681,814, a formulation patent (4.53 years added to Oct. 2014); 2028, based on extension of 6,331,414, a formulation patent (4,828 days/13.2 years added to Oct. 2014); |
U.S. Patent Expiration Year: | not calculable* |
U.S. Biosimilars Data Exclusivity Expiration: | 2017 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2012 |
U.S. Biosimilars Launchability Year: | 2017 |
U.S. Biobetters Launchability Year: | 2017 |
Biosimilars/biobetters-related EU Patents: | The EPO deemed IGF unpatentable due to prior disclosures; other use, formulation, etc. patents may apply; 2005 arbitrarily used as expiration date |
EU Patent Expiration Year: | 2005 |
EU Biosimilars Data Exclusivity Expiration: | 2017 |
EU Biosimilars Orphan Exclusivity Expiration: | 2017 |
EU Biosimilars Launchability Year: | 2017 |
EU Biobetters Launchability Year: | 2005 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth hormone deficiencies
hormones
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
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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