Status: approved in U.S., but withdrawn due to patent infringement

Organizations involved:

Insmed Inc. – Manuf.; R&D; Tech.; World mark.

Avecia Ltd. – Manuf.

BioGrowth, Inc. – R&D; Tech.; Former

Celtrix Pharmaceuticals, Inc. – R&D; Tech.; Former

Tzamal Pharma - Mid. East mark.

Elan plc - R&D; Former

Green Cross Corp. – Former

Elan Corp., plc – Former

Tercica, Inc. – Patent dispute

Ipsen S.A. –Parent

Genentech, Inc. – Patent dispute

Cephalon, Inc. – Tech.

Cross ref.: See the entries for other insulin-like growth factor products.

Description: iPlex is an aqueous formulation of mecasermin rinfibate, a binary protein complex of recombinant nonglycosylatated insulin growth factor-1 (IGF-1; somatomedin-1) noncovalently bound to recombinant insulin-like growth factor binding protein-3 (IGFBP-3), with both proteins separately expressed by transformed Escherichia coli (E. coli) bacteria . The IGF-1/IGFBP-3 complex mimics the native IGF-1/IGFBP-3 complex, including its biological effects, serving as a method for delivery of IGF-1. In solution, IGF-1 and IGFBP-3 naturally bind stoichiometrically in a 1:1 ratio (even though both the C- and N-terminal fragments of IGFBP-3 appear to bind IGF-1) to form mecasermin rinfibate. The IGF-1/IGFBP-3 complex has a molecular weight of 36.381 kDa and a calculated molecular formula of C1231H1967N371O384S20.

IGF-1 is composed of 70 amino acids in a single chain with three intramolecular disulfide bridges and molecular weight of 7.649 kDa (and is further discussed in the other IGF-1 product entries).

IGFBP-3 is a cysteine-rich 264-amino acid protein, preceeded by a 27-amino acid signal sequence, with the same sequence as endogenous human IGFBP-3, molecular weight of 28.732 kDa, and is indistinguishable in sequence and other properties from the IGFBP-3 in human plasma. However, endogenous human IGFBP-3 has three glycosylation sites, while the IGFBP-3 in mecasermin rinfibate is not glycosylated, since it is expressed in E. coli. Glycosylated and nonglycosylated IGFBP-3 bind IGF-1 with similar affinities, and since the IGF-1 portion of the complex has the primary biological activity, the nonglycosylation of IGFBP-3 does not significantly alter biological activity of IGF-1/IGFBP-3. Endogenous IGFBP-3 contains 18 cysteine residues that are all paired in disulfide bonds to form the biologically active molecule, but the pairings have not been fully elucidated.

iPlex is supplied as a 0.6 mL, 36 mg/0.6 mL preservative-free sterile solution in single dose glass vials.. Each box contains 35 vials. Mecasermin rinfibate is temperature-sensitive and iPlex must be stored frozen at -70°C (-94ºF) while in the distribution chain. The patient must be instructed to keep the medication frozen while transferring it to his/her home freezer (-20°C; -4ºF). Frozen (-70°C). iPlex from the distributor can be transported on dry ice to the patient’s home freezer, and must remain in the patient’s home freezer until time of use. iPlex can be stored frozen up to two months at constant temperature (-20°C, -4ºF). For use, iPlex is removed from the freezer and thawed at room temperature (20-25ºC; 68-77ºF) for 45 minutes prior to use. After thawing, the vial is allowed to reach room temperature prior to injection (~45 minutes). The vial is swirled in a gentle rotary motion to ensure content uniformity and used within one hour after the vial reaches room temperature. iPlex can not be used if it has been at room temperature for more than two hours.

Biological.: IGF-I/IGFBP-3 serves to deliver IGF-I, which regulates essential metabolic and anabolic (growth promoting) processes, including glucose uptake and tissue regeneration. IGF-I and IGFBP-3 are normally bound in vivo. The IGF-I/IGFBP-3 complex mimics the natural, endogenous form and method for delivery of IGF-1. Protease enzymes cleave the complex in response to certain stresses and release IGF-1.

The primary effect of IGFBP-3 in the mecasermin rinfabate complex is the modulation of IGF-1 action. There are no known direct growth-promoting effects of IGFBP-3. In normal human circulation, less than 2% of total IGF-1 exists in the free form. Most circulating IGF-1 is found in association with the growth hormone (GH)-dependent binding protein IGFBP-3, and this binary complex further associates with a third serum protein, the GH-dependent acid-labile subunit (ALS), to form a non-covalent ternary complex of ~150 kD, which represents the natural physiologic reservoir of IGF-1. The ternary complex consists of one molecule each of IGF-1, IGFBP-3, and ALS. The half-life of IGF-1 in the ternary complex is > 12 hr. Proteolytic cleavage of IGFBP-3 and interaction of the ternary complex with proteoglycans release IGF-1 from the ternary complex.

The IGFBP-3 mature protein is composed of 264 amino acids. In humans, it comprises at least two naturally occurring allelic variant proteins, in which the fifth amino acid residue of the mature protein is either glycine or alanine (referred to as Gly5 IGFBP-3 and Ala5 IGFBP-3, respectively). When produced by human or other mammalian cells (e.g., CHO cells), the protein is post-translationally modified by up to three N-linked glycosylations at three separate sites. The asparagine residues of IGFBP-3 (positions 89, 109 and 172) are the normal N-linked glycosylation sites. When produced in bacteria, the protein is not glycosylated. IGFBP-3 also includes variants of the protein, for example variants in which the amino acid sites of the normal N-linked glycosylation are altered to another amino acid.

Administration IGF-1 as an IGF-1/IGFBP-3 complex reduces many of the side effects seen when IGF-1 alone is administered directly. The complex also has a longer in vivo half-life than IGF-1 alone, and mimics the natural in vivo form of IGF-1/IGFBP-3.

The normal human blood level of IGF-1 is 100-200 ng/mL, with levels declining with age. Peak plasma levels of IGF-1 have been shown to be safely increased up to 35-fold by administration of IPlex (IGF-1/IGFBP-3). A single 1.0 mg/kg dose of iPlex has been shown in trials to deliver the same amount of IGF-1 as two standard daily injections of IGF-1. IGF-1/IGFBP-3 reaches peak plasma concentrations at 15-19 hours, vs. 8 hours for rIGF-1.

Clinical trials comparing IGF-1 and IGF-1/IGFBP-3 have not been performed, but the two have been compared in animals. Equivalent doses of IGF-1/IGFBP-3 and IGF-1 (125 µg/day of IGF-1) administered subcutaneously to Sprague-Dawley rats with corticosteroid-suppressed wounds showed that IPlex was a more effective promoter of wound healing in this model. All measured parameters were increased substantially more by IPlex than by IGF-1. The effect of intravenous doses of IPlex (5 µg/g) and recombinant IGF-1 (15 µg/g) administered twice daily for 3 days on starvation-induced protein synthesis was examined in Sprague-Dawley rats. IPlex, but not rhIGF-1 alone, significantly stimulated muscle protein synthesis. The plasma concentration of IGF-1 was 20% higher in IPlex-treated animals compared with those receiving rhIGF-1, and plasma concentrations of amino acids were increased in IPlex-treated animals.

Nomenclature: Insulin-like Growth Factor-1/IGBP-3, rDNA [BIO]; iPlex [TR]; SomatoKine [TR former]; mecasermin rinfibate [USAN INN]; insulin-like growth factor I (human), complex with insulin-like growth factor-binding protein IGFBP-3 (human) [CAS]; 433977-72-1 [CAS RN 9CI]; 478166-15-3 [CAS RN from USAN]; insulin-like growth factor-1 binding protein 3, insulin-like growth factor-1 carrier protein [SY]; somatomedin C, complex with somatomedin-1 binding protein 3 [SY]; rhIGF-I/rhIGFBP-3 [SY]; IGF-I/rhIGFBP-3 [SY]

Companies.: SomatoKine, now iPlex, was originally developed by BioGrowth, Inc., which in 1991 sold its rights to Celtrix Pharmaceuticals, which was acquired by Insmed Pharmaceuticals in June 2000. Insmed was founded in the late 1980s by Dr. J. Larner, University of Virginia, and P. Thomas, a former stockbroker.

In August 2002, Insmed concluded a manufacturing agreement with Avecia Ltd. (now Fuji Diosynth), with large-scale manufacture at Avecia Advanced Biologics Centre (Billingham, U.K.), including scale-up to 10,000 liters.

Insmed operates a recombinant protein manufacturing facility in Boulder, CO, formerly run by Baxter International, for commercial manufacture of iPlex. The combination of manufacturing by Insmed and Avecia is expected to meet the need for IPlex as it is commercialized.

Japanese rights were licensed in April 1995 to Welfide Corp. (Green Cross; Yoshitomi Pharmaceutical Industries) which was merged into Mitsubishi Pharma in Oct. 2001, and is now part of Probitas Pharma. Preclinical development for osteoporosis in Japan began in May 1995. The first Phase I trial began in July 1996, but no major development activities have been reported after 1998.

In April 1999, Elan plc (acquired in 2013 by Perrigo) established a joint venture with Celtrix (now Insmed) for the development of Somatokine for steoporosis using Elan’s MediPad delivery system. The joint venture was initially 80.1% owned by Celtrix and 19.9% owned by Elan. No activity with this collaboration has been reported since early 2000, and the agreement was later reported to have been terminated.

Tzamal Pharma holds exclusive IPlex marketing rights for certain Middle East countries.

Insmed has sought alternative methods for cheaper large-scale manufacture of iPLEX. In April 2006, Insmed contracted with Dow Chemical Co. for development of methods for manufacturing both recombinant IGF-1 and IGFBP-3 using its Pfenex technology, based on a Pseudomonas bacterial expression system. In July 2006, Insmed concluded an agreement with Phyton Biotech, Inc., a DFB Pharmaceuticals affiliate, for the development of plant cell fermentation technology for manufacture of iPLEX. Phyton’s German subsidiary, Phyton Biotech GmbH, operates the world’s largest commercial cGMP manufacturing facility for plant cell fermentation, with bioreactors up to 75,000 liters in size.

In March 2006, after having lost a U.S. patent infringement dispute (see the Tech. transfer section) brought by Tercica (and Genentech), Tercica, Insmed and Genentech, Inc. entered into a Settlement, License and Development Agreement that resolved all outstanding litigation among the companies, including the patent infringement suits brought by Tercica and Genentech against Insmed in the U.S. and U.K., and suits filed by Tercica and Insmed charging the other with improper marketing of their IGF-1 products. The settlement included Insmed no longer providing iPlex to patients with severe Primary IGF-1 Deficiency and other short stature indications:; Insmed withdrawing its iPLEX marketing authorization application for severe Primary IGF-1 Deficiency in the European Union; and Tercica and Genentech waiving the damages award by the jury in the U.S. patent infringement litigation. Through licensing and development rights granted by Tercica and Genentech, Insmed will have freedom to operate regarding the manufacture, development and commercialization of iPlex for certain non-short stature indications: including severe insulin resistance, myotonic muscular dystrophy and HIV associated adipose redistribution syndrome (HARS), subject to opt-in rights and royalty provisions for Tercica and Genentech. But, due to patent infringement, Insmed is no longer be able to provide iPlex in the U.S. for any of the following.

Regarding future development, the companies formed joint development and joint commercialization committees to guide the development and commercialization of iPlex in non-Tercica/Genentech indications:. Tercica (along with Ipsen, for Ipsen’s Increlex territory) and Genentech will have the right to opt into Insmed’s development and commercialization of each non-Tercica/Genentech Indication up to 90 days after Insmed provides “Phase III-enabling” clinical data. Tercica will have the first right to opt into orphan indications:, and Genentech will have the first right to opt into non-orphan indications:. If Tercica does not opt into an orphan indication, Genentech will have the right to opt-in. Similarly, if Genentech does not opt into a non-orphan indication, Tercica will have the right to opt-in. In the case of an opt-in, Insmed will retain development control prior to approval, and Tercica or Genentech would gain commercial control after approval. If the opt-in is exercised by Tercica, Insmed would be reimbursed 50% of its development costs for the indication and further development costs would be shared 50:50. Upon commercialization, Insmed and Tercica will split profits 50:50 after expenses, including sales-based tiered royalties of 6%-15% to Genentech. If the opt-in is exercised by Genentech, Insmed would be reimbursed 50% of its incurred development costs for the indication. Subsequent development costs and profits will be split 50:50, but no royalty will be owed to Tercica. If neither Tercica nor Genentech opts in, Insmed will pay a 4% royalty on all commercial sales of the approved drug to Genentech

Outside the U.S. and Canada, Insmed will continue to provide iPlex to physicians through its Expanded Access Program for non Tercica/Genentech indications: (excluding severe insulin resistance) and ALS in Italy. Any cost reimbursement obtained from this program is subject to a tiered royalty of 4% to 15% shared between Tercica, Genentech and Ipsen.

In March 2009, Insmed sold its Boulder, CO, biopharmaceutical manufacturing facility and some candidate biosimilars to Merck & Co., Inc., leaving the company without a means for Iplex manufacture.

Manufacture: Insmed’s methods for manufacture of IGF-1/IGFBP-3 are broadly described at its Web site. The below description of the manufacturing processes has been adapated from this and Examples 3 and 4 of U.S. 6,017,885 (assigned to Celtrix/Insmed). IGF-1/IGFBP-3 is manufactured using two independent fermentations, one for IGF-I and another for IGFBP-3. Note, some or much of the patent-derived details provided below may have been modified and improved for large-scale manufacture.

Escherichia coli K-12 strain W3110 lysogenized with DE3 carries the gene for T7 RNA polymerase under the control of the lacUV5 promoter. This host strain was transformed with plasmid pER10088 bearing IGF-I cDNA by selection for tetracycline-resistance. Plasmid vector pER10088 contains an open reading frame (ORF) comprising (in order 5’ to 3’) an ATG triplet (initiation), the 76 codons of yeast ubiquitin, and 70 synthetic codons of mature human IGF-1; for the expression of ubiquitin–IGF-I fusion protein. E. coli is cultured in a 1,500 L fermenter. Process parameters such as dissolved oxygen, temperature, pH and nutrient levels are controlled within precise limits to optimize both cell growth and protein production. The cells are harvested and disrupted, e.g., by milling or sonication. A small amount of polyethyleneimine is added to the lysate, this is centrifuged, and the resulting solids used for further purification. The filtrate is diluted and subjected to a DNA removal step using protamine sulfate and Q-Sepharose chromatography. Ubiquitin protein peptidase is added to the mixture to release IGF-I from the ubiquitin–IGF-I fusion protein, and IGF-I is refolded overnight at ambient temperature. As described in 6,017,885, this refolding yields about 40% of the correctly refolded IGF-I compared to the initial amount of IGF-I, but U.S. 5,789,547 (discussed in the Tech. transfer section) reports a method achieving much higher yields. Refolded IGF-I solution is clarified, buffer is exchanged using ultrafiltration, and the solution is eluted through a cation exchange chromatography column. Fractions of pure IGF-I are pooled and acidified to pH 2.5, filtered through a 0.2 µm filter, and passed through a Vydac C-4 chromatography column. Fractions containing purified IGF-1 are assayed by SDS-PAGE, pooled and lyophilized.

IGFBP-3 is manufactured using transformed CHO cells. After culture in a 1,500 fermenter, harvest, and cell disruption, IGFBP-3 is extracted with buffer and filtered through a Sartorius 0.8 µm filter. The filtrate is diluted with buffer and subjected to a DNA removal step using protamine sulfate, with protamine sulfate precipitate removed by filtration, and IGFBP-3 subjected to refolding, e.g., at 0.5-1 mg/ml protein concentration, 1.0 to 1.5 M GdHCl at pH 8-9 in the presence of Tris buffer at 20 to 50 mM, having reducing/oxidizing agents molar ratio of 1. As described in 6,017,885, this refolding yields about 60% of the correctly refolded IGF-I compared to the initial amount of IGF-I, but U.S. 5,789,547 (discussed in the Tech. transfer section) reports a method achieving much higher yields. Refolded IGFBP-3 solution is clarified, buffer is exchanged using an ultrafiltration system, and the solution passed through a cation exchange column. Fractions of high concentration IGFBP-3 are pooled, the salt concentration increased to 0.6 M with ammonium sulfate, and the solution passed through a hydrophobic interaction chromatography matrix column. Appropriate fractions were then pooled and saved. These fractions are brought to 0.1% trifluoroacetic acid (TFA), and the solution is passed through a C4 RP-HPLC column equilibrated with 0.1% TFA in water. Fractions containing IGFBP-3 were pooled and lyophilized.

Formation of IGF-1/IGFBP-3 complex in the Final Purification step is accomplished by simply mixing IGF and IGFBP-3 in an aqueous solution including pH buffer salts and dissolved osmolyte salts (e.g., NaCl). The complex forms quickly without any further manipulation. The complexed product is then processed to target purity by means of a final chromatography step. This is followed by a final formulation step, in which the complexed product is exchanged into the excipient solution by ultrafiltration/diafiltration (UF/DF). The product and excipient concentration in the formulated bulk are optimized to achieve maximal dating (shelf life).

Filling of the final vials is accomplished at a third party contractor. The formulated bulk is sterile filtered, aseptically filled into sterile vials, and capped. The vials are labeled and stored in quarantine until released. Final vials are tested to ensure purity, potency, identity, quality, and composition. When all test results have passed the final specifications, quality assurance (at the Bolder, CO, facility) releases the final vials for distribution.

FDA class: Drug NDA

Approvals: Date = 20051212; original NDA, orphan drug status

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

iPlex (mecasermin rinfabate [rDNA origin] injection) is indicated for the 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 and basal IGF-1 standard deviation score ≤ -3 and normal or elevated growth hormone.

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.

iPlex 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 iPlex treatment. iPlex is not a substitute for GH treatment.

Status: [Note, as discussed in the Companies and and Tech. transfer sections, iPlex is no longer marketed (for its approved indications: in the U.S.), with this resulting from settlement of a patent infringement dispute with Genentech and Tercica].

An NDA for the treatment of growth hormone insensitivity syndrome (GHIS; Laron syndrome) with orphan status was accepted on Jan. 3, 2005, with a priority review PDUFA date (action target date) of July 3, 2005. However, on Sept. 28, 2005, FDA issued an approvable letter requesting more chemistry, manufacturing, and controls (CMC) information. The NDA was approved on Dec. 12, 2005 (approval time = ~.95 year). iPLEX was launched in the U.S. on May 25, 2006.

Note, prior to approval, during the evaluation process, FDA changed the name of the official indication of iPlex for orphan drug designation from Growth Hormone Insensitivity (GHIS) to Severe Primary IGF-1 Deficiency, the same indication as approved for Increlex. The FDA’s approval of IGF-1/IGFBP-3 with orphan status was not affected by the prior approval of Increlex (IGF-1), i.e., FDA considered each to be unique, different products. Both FDA and EMEA/European Union (EU) have granted orphan status to iPlex for severe primary IGF-1 deficiency.

A European Union MAA with orphan status was filed, was validated (accepted) in July 2006, but has been withdrawn as part of the patent dispute settlement (see the Companeis and Tech. transfer sections).

In Jan. 2007, the Italian Ministry of Health requested Insmed make iPLEX available to physicians in Italy to treat patients with amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease; an unapproved indication). The request came after several Italian court rulings ordered the Italian National Health System to provide Iplex to specific ALS patients who had petitioned the court. Through an agreement with Cephalon, which holds a European patent concerning IGF-I for treatment of ALS, Insmed provides iPLEX to physicians in Italy through an expanded access program, with Insmed receiving payment for drug from the Italian health authorities. As of March 2008, the expanded access program included 15 physicians and ~70 subjects, and Insmed received cost recovery of $5.4 million for iPlex in 2007 (roughly $73,000/patient).

In Dec. 2007, FDA granted iPlex orphan drug status for treatment of myotonic muscular dystrophy (MMD), the only indication for which trials were ongoing.

In March 2009, FDA granted an IND allowing patients with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease also known as Lou Gehrig’s Disease, or ALS, to have access to Iplex. At the time, Iplex was not beining marketed in the U.S. because of a court order related to patent infringement (see the Tech. transfer section). FDA and Insmed agreed that access to Iplex for investigational use in patients with ALS could occur in two ways under Investigational New Drug applications (INDs):

1) Single-patient INDs requesting “compassionate use” of Iplex for treatment of named patients with ALS, received and date-stamped by FDA’s document room by close of business on March 6, 2009, will be allowed to proceed, and Insmed has agreed to supply Iplex to those patients; and

2) The remaining supply of Iplex, which is very limited, will be used by Insmed to conduct a clinical trial under an IND in which other patients with ALS who are interested in receiving Iplex treatment will be randomly assigned to receive it through a lottery system. FDA agreed to allow Insmed to submit a request for cost recovery under existing IND regulations to offset the costs associated with conducting the planned clinical trial.

In July 2009, Insmed cease the supply of Iplex to any new patients and reported it would not initiate further clinical trials with Iplex. Insmed determined that its limited inventory on hand must be conserved for the treatment of existing patients. Following the previously announced sale of Insmed's Boulder, Colorado manufacturing facility to Merck & Co., Inc. in March 2009, Insmed no longer has the capability to manufacture Iplex. And any agreement with a third party to undertake the manufacture of Iplex, if it was economically feasible and could be arranged, would not result in production of additional quantities for at least 12 to 18 months.

In June 2009, there are approximately 70 patients receiving Iplex, 12 in the U.S. and the remainder around the rest of the world. Most of the patients were receiving Iplex pursuant to a court-ordered Extended Access Program (EAP) for Amyotrophic Lateral Sclerosis (ALS) in Italy. The 12 U.S. patients were being treated for ALS under single patient Investigational New Drug (IND) applications approved by FDA. Insmed believed that it has sufficient inventory to supply these patients for no more than 24 months. Insmed intended to analyze the on-going data collected for various indications:, including myotonic muscular dystrophy and ALS, and assess the overall Iplex development program, including possible manufacturing options with third parties and possible future clinical trials. Initiation of the Phase II clinical trial for ALS patients in the U.S. that had been discussed with FDA earlier this year was postponed while the Company performs these assessments.

Tech. transfer: A large number of patents have been granted concerning IGF-1, IGFGP-3, fragments and variants, and complexes of IGF-1/IGFBP-3, many of these claiming use for various indications:. For example, IGF-I/IGFBP-3 patents assigned to Celtrix/Insmed or pending include claims for the treatment of diabetes mellitus (e.g., U.S. 6,040,292); pharmaceutical formulations (U.S. 6,436,897); use to promote bone formation and remodeling (U.S. 6,017,885); treatment of diabetes types 1 and 2 and insulin resistance (U.S. 6,040,292; also 5,674,845 and 5,686,408). U.S. 5,563,046, assigned to Celtrix (Insmed) describes use of interleukin-1 ( IL-1)-like fusion polypeptides to increase the solubility and activity of recombinant polypeptides using ubiquitin as a linker.

U.S. 5,789,547, “Method of producing insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) with correct folding and disulfide bonding,” Aug. 4, 1998, assigned to Celtrix (Insmed) provides a method for proper refolding of IGF-I and IGFBP-3 as IGF-1/IGFBP-3 complex by mixing them in a cofolding reaction providing high yields of correctly folded protein. Neither Insmed’s brief discussion of the manufacturing process at its Web site, nor 6,017,885 (from which manufacturing information above was extracted) mention use of this process, which involves denaturing, reducing, and oxidizing mixtures of IGF-1 and IGFBP-3

On Dec. 20, 2004, Tercica (now meged into Ipsen S.A.) and Genentech [the original developers of Increlex (IGF-1); see related entry] initiated patent infringement proceedings against Insmed Inc. and Avecia Ltd. as co-defendants in the U.K. High Court of Justice (Chancery Division Patents Court). The companies allege that commercial manufacture of IPlex for the treatment of GHIS 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 denied from motions from Tercica/Genentech concerning this suit and from a related patent revocation request brought by Insmed and Avecia against Genentech, indicating that the issue of patent validity could not be decided on summary judgment and at this early stage of the case. The patent’s validity will now be thoroughly examined at trial.

On Dec. 23, 2004, Tercica, along with Genentech, initiated patent infringement proceedings (Tercica Inc. v. Insmed Inc.) against Insmed Inc. in the U.S. District Court for the Northern District of California. The companies allege that manufacture, use, and importation of iPlex for the treatment of GHIS infringe and/or will infringe U.S. 5,187,151; 6,331,414 and 5,258,287, assigned to Genentech and licensed to Tercica. These patents include claims for the combination 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 patent infringements from being filed against a drug that is being tested in clinical trials, that the filings were an attempt to delay its NDA, lack of an inventive step in these patents, and other reasons. On February 16, 2005, Tercica filed an amended complaint, adding an infringement allegation against Insmed with respect to 5,528,287, or the ‘287 patent. In April 2005, the U.S. District Court 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. In May 2005, Tercica, with Genentech, Inc. as co-plaintiff, ffiled a motion for a preliminary injunction (continuing the case) against Insmed Inc. However, in June, after FDA delayed the review/PDUFA date for for Tercicas’ product, this motion was withdrawn. Insmed could again seek a preliminary injunction (particularly now that orphan drug exclusivity for its product will not prevent marketing of Tercica’s product).

In June 2006, the court granted Tercica motions for partial summary judgment, ruling that Insmed’s process for making iPLEX infringed Increlex’s 6,331,414 process patent. The court also agreed that Tercica’s “method of use” patent (5,187,151) was valid over “prior art.” meaning its applies to products available prior to the patent issuance. These actions made it much more difficult for Insmed to mount its case.

In Dec. 2006, a U.S. District Court for the Northern District of California jury ruled in favor of Tercica (and Genentech), finding that iPlex from Insmed had infringed Tercica/Genentech patents 5,187,151 (‘151 patent) and 6,331,414 (‘414 patent). Prior to the trial, the Court had ruled that Insmed’s process for making the IGF-1 in iPlex literally infringes three claims of the ‘414 Patent, and Insmed admitted that it infringes on three additional claims. In its ruling, the jury ordered Insmed to pay Tercica $7.5 million upfront, 15% royalties for past sales of Iplex of up to $100 million, and 20% royalties for sales greater than $100 million.

Shortly after this infringement ruling against Insmed, the companies concluded an out-of-court licensing and development agreement in order to end the dispute. See the Companies section above for the details of the settlement. Tercica and Genentech waived the damages awarded by the jury. Insmed agreed to stop marketing of Iplex to patients with severe Primary IGF-1 deficiency and other short stature indications: (the currently approved indications:) and to withdraw its then-pending marketing application in the European Union. Insmed will have freedom regarding manufacture, development and commercialisation of the iPLEX for certain non-short stature indications:, subject to opt-in rights and royalty provisions for Tercica and Genentech. The parties will form a joint-development committee to guide the development and commercialization of Iplex in non-Tercica/Genentech indications:. The agreement is in effect until the later of 2018 or the expiration of any subsequent Tercica/Genentech issued patents that cover iPLEX or its indications:.

Chiron Corp. holds a U.S. patent concerning IGF-1 expression in yeast. See the Tech. transfer section of the Myotrophin entry. Insmed uses bacterial expression.

Cephalon holds some patent(s) in Europe related to IGF-1 use for treatment of amyotrophic lateral sclerosis (ALS), and has licensed this to Insmed to allow its expanded asssess program of iPlex in Italy.

Insmed lacks composition-of-matter, e.g., gene/protein sequence, patent protection for IGF-1, which is apparently in the public domain. See the IGF-1 product entries – Increlex and Myotrophin – for further IGF-1 patents.

Trials: Clinical use of IPlex has been studied or four different growth hormone insensitivity syndrome (GHIS; Laron syndrome), diabetes (types 1 and 2), osteoporosis and severe burns. However, IPlex is currently only in development for GHIS (already approved) and diabetes. Phase I clinical trials with IGF-1/IGFBP-3 were initiated in May 1999. In June 2002, a dose-ranging Phase II trial was initiated in children with GHIS. Other trials have included several Phase II trials for diabetes, a Phase II trial for osteoporosis, and four trials for burn treatment. These clinical studies have shown IPlex to be well tolerated and have fewer side effects than IGF-1

On July 20, 2004 Insmed reported top-line results from a six-month data analysis of the pivotal open-label, international Phase III GHIS clinical trial showing a statistically significant increase (p < 0.0001) in height velocity in children with GHIS receiving IPlex as a once-daily subcutaneous injection. This prospectively designed Phase III trial evaluated the safety and efficacy of IPlex in prepubescent children with GHIS. The profile of activity observed at six months with once-daily injections of IPlex was similar to that observed by Pharmacia (now Pfizer) in their prior pivotal GHIS study of IGF-1 in which twice-daily injections of IGF-I were given to a similar population of patients. IPlex was well tolerated and safely increased and sustained circulating IGF-I levels in the study population.

Development of IPlex for mainstream diabetes treatment has effectively been halted. Small studies have shown that IPlex is efficacious when given by injection rather than by infusion, but a dose of 2 mg/kg is required for sufficient efficacy. This dose would result in the price of IPlex too high for routine use. Also, diabetic patients currently receiving insulin are unlikely to prefer additional daily injections of IPlex when there is an increasing range of orally active insulin sensitizers available.

In April 2005, Insmed began an open-label dose-ranging Phase II trial of once daily IGF-I for treatment of type A extreme insulin resistance. The primary efficacy endpoints of the trial are improvement in glycemic control, improvement in insulin sensitivity, reduction in hemoglobin A1c, and improvement in body composition.

In Sept. 2005, Insmed updated results from its pivotal, prospective, multicenter Phase III trial in 25 evaluable patients with severe primary insulin-like growth factor-I (IGF-I) deficiency. In a subset of 16 patients having received a fixed low dose of up to 1 mg/kg of iPlex, a better height velocity (faster growth rate) was observed in those whose IGF-1 blood levels reached a normal target range. The increase in height velocity at 12 months was 8.3 cm/yr for those with normal IGF- 1 levels vs. 5.6 cm/yr for patients with persistently low levels on the low fixed dose (p <0.0001). A subset of 9 patients, whose dose was increased up to 2 mg/kg based on IGF-1 levels, had an average 9-month annualized height velocity of 8.2 cm/yr compared to pretreatment velocity of 2.2 cm/yr (p <0.0001).

In Jan. 2006, Insmed initiated a U.S. Phase II study in 30 patients with once-daily subcutaneous injections of iPlex. The trial is determining the optimal dose of once-daily subcutaneous injection of iPlex during a 24-week, dose escalation portion of the trial, followed by 24-week, placebo-controlled, double-blind, fixed-dosing.

In April 2007, Insmed reported positive results form an investigator-sponsored Phase II trial with iPLEX for treatment of HIV-infection-associated adipose redistribution syndrome (HARS), a condition involving the loss of adipose, or fat tissue, around the extremities and facial area and increased fat tissue deposits in the abdominal area.

In May 2006, Insmed presented updated results from its pivotal Phase III trial of iPLEX injection once daily in children with severe disease. iPLEX treatment resulted in statistically significant, dose-dependent increases in height velocity (growth rate), with a favorable safety profile. The he mean height velocity for the dose group titrated with up to 2 mg/kg/day increased from 2.0 cm/year pre- treatment to 8.3 cm/year during treatment. Children with genetic and acquired forms of growth hormone insensitivity appeared to respond equally well to treatment.

In June 2009, Insmed reported disappointing results from an exploratory U.S. Phase II clinical trial evaluating Iplex in patients with myotonic muscular dystrophy ("MMD"). The randomized, double-blind, placebo-controlled Phase II trial conducted in 13 centers across the U.S. enrolled 69 patients with MMD for a six-month period. As this was an exploratory trial, no primary endpoint was pre-defined. The trial explored measures of endurance, using the six-minute walk test, muscle function and strength, cognitive function, gastrointestinal function, pain, quality of life, insulin sensitivity, lipid metabolism, and safety and tolerability of Iplex. Iplex did not exhibit a statistically significant improvement in the functional measure of endurance by the six-minute walk test, muscle function, muscle strength, or quality of life in any of the tests utilized in this study. Based on the limited number of subjects enrolled with significant impairments in cognitive function, gastrointestinal function or pain, Insmed was unable to reach any conclusions regarding the effects on these endpoints. Iplex did, however, demonstrate improvements in standard measures of insulin sensitivity and reductions in fasting glucose, fasting insulin, cholesterol and triglycerides, which is consistent with the expected metabolic profile of insulin-like growth factor. Iplex also resulted in anabolic effects of increased body mass index and higher levels of testosterone. The drug was well tolerated in MMD subjects and demonstrated a safety profile consistent with previous studies of Iplex. Based on the metabolic improvements observed in patients treated with Iplex in this trial, the Company intended to apply for a grant from the Muscular Dystrophy Association (MDA) to facilitate an additional Phase II trial focused solely on a subset of MMD patients with severe insulin resistance who, based on the results of this trial, may be more likely to benefit from Iplex treatment. Alternative methods of assessing muscle function will be considered for the proposed trial.

Medical: iPlex dosage and administration should be individualized for each patient. iPlex is administered by subcutaneous injection at an initial dose of 0.5 mg/kg, to be increased into the therapeutic dose range of 1 to 2 mg/kg, given once daily. iPlex can be given in the morning or in the evening but should be administered at approximately the same time every day and the patient should maintain a regular, balanced diet. Dosage can be titrated up to a maximum of 2 mg/kg daily based on measurement of IGF-1 levels obtained 8-18 hours after the previous dose. Physicians should target on-treatment IGF-1 levels of 0 to +2 SD score for age. Dosage should be adjusted downward in the event of adverse effects (including hypoglycemia) and/or IGF-1 levels greater than or equal to 3 standard deviations above the normal reference range for IGF-1.

Disease: Myotonic muscular dystrophy (MMD) affects approximately 37,000 Americans, and nearly 60,000 people in the European Union. MMD is a genetic disease characterized by endurance loss, muscle wasting, weakness, pain, cognitive impairment and gastro-intestinal dysfunction. Muscular Dystrophy is diagnosed at the rate of 50,000 to 250,000 persons annually in the U.S., and MMD is the most common form of the disease. DM1, which occurs in approximately 98% of MMD cases, is caused by an excessive number of cytosine, thymine and guanine (CTG) repeats on Chromosome 19. There is currently no cure and no specific treatment has been developed to satisfactorily reverse or ameliorate the common symptoms associated with the disease.

Market: As discussed in the Tech. transfer section above, as part of a patent infringement settlement, Insmed removed iPLEX from the market (for its approved indication).

The 2007 Average Wholesale Price (AWP) is $90.00/vial, with a Direct Price (discounted price) of $72.00; and $3,150.00/box of 35, with a Direct Price of $2,520.00 (Red Book, 2007).

Total 2006 sales by Insmed were about $1.2 million. Total 2005 sales of iPlex were negligible, with total 2005 company revenue of $131,000.

In March 2007, when IPLEX was withdrawn (see the Status and Tech. transfer sections), over 100 children in the U.S. were receiving iPLEX.

In Nov. 2006, prior to iPLEX essentially being withdrawn from the the market (for its approved indications:), Friedman, Billlings and Ramsey (FBR) analysts had projected worldwide 2007 sales of $15 million, 2008 sales of $43 million, and 2009 sales of $98 million.

Prior to its market withdrawal, it was expected that iPlex treatment of GHIS may come to be accepted as a substitute or adjunct to the use of recombinant growth hormone for GHIS treatment. However, this orphan product was unlikely to attain a high level of sales. None of the various forms of GHIS are particularly prevalent and IPlex may be found useful in only some of these forms (although the common genetic deficiency in IGF-1 suggests that it will be efficacious in all groups of GHIS patients). See the Increlex entry above for further discussion of the market for IGF-1-type products.

Also, prior to market withdrawal, some analysts have suggested that iPlex may not be that profitable or as profitable as Increlex. The necessary dose of 2 mg of protein per kg of body weight is eight times the amount of protein as an Increlex dose. Most of this is actually due to the BP3 portion of the molecule, which is a larger protein than the IGF-1 portion and more difficult to manufacture.

In June 2006, Tercica filed false advertising claims in federal court against Insmed regarding its marketing of iPLEX, with Insmed claiming advantages due to its once-daily administration. 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

In 2007, Insmed completed an external assessment of the total market for MMD treatments that indicated that the market for myotonic muscular dystrophy (MMD). Based on responses from neurologists interviewed, patients afflicted with MMD could number between 28,300 and 37,000 by 2010, and the total market for MMD treatments could be as high as between $800 million and $1.4 billion.

Ongoing: As of April 2008, after the product was withdrawn from the U.S. market due to patent infringement (see Tech. transfer section), iPlex was in clinical trials for myotonic muscular dystrophy (MMD). Positive results had been reported from a Phase II investigator-sponsored study in six patients with MMD; and a 24-week, multi-center, randomized, double blind, placebo-controlled Phase III trial wa ongoing in 60 patients with MMD. Insmed had received a grant of $2.1 million from the Muscular Dystrophy Association (MDA) to cover a substantial portion of trial's costs. iPlex was also in devlopment for HIV associated Adipose Redistribution Syndrome (HARS). IGFBP-3 (uncomplexed) is also in preclinical development for various cancer indications:.