Status: approved; marketed

Organizations involved:

Eyetech Pharmaceuticals, Inc. – Manuf.; R&D; Tech.; USA mark.

Valeant Pharmaceuticals International, Inc. – Parent OSI Pharmaceuticals, Inc. – Parent

Pfizer, Inc. – World mark. (ex-U.S.)

Raylo Chemicals Inc. – Manuf.

Fujifilm Diosynth Biotechnologies - Manuf.

Gilead Sciences, Inc. – Manuf. other; R&D; Tech.; Parent

Degussa AG – Former

NeXstar Pharm,, Inc. – R&D; Tech.; Former

Isis Pharmaceuticals, Inc. – Tech.

Nektar Therapeutics, Inc. – Manuf. other

University of Alabama – Tech.; Patent dispute

Enzon Pharmaceuticals, Inc. – Tech.

Drug Royalty Corp. – Tech.

Cross ref.: See the entry for VEGF Mab, rDNA (Avastin), a VEGF monoclonal antibody, from Genentech.

Description: Macugen is an aqueous formulation of pegaptanib sodium, the sodium salts of a 2’-fluoropyrimidine RNA-based synthetic phosphorothioate oligonucleotide aptamer (antibody-like polynucleotide) with binding specificity for vascular endothelial growth factor (VEGF) complexed by pegylation (covalent attachment of two methyl polyethylene glycol or PEG side chains) via a linker group. Pegaptanib is a covalent conjugate of an oligonucleotide with phosphorothioate internucleoside linkages of twenty-eight nucleotides in length that terminates in a pentylamino linker, to which two 20 kDa monomethoxy polyethylene glycol (PEG) units are covalently attached via the two amino groups on a lysine residue of the polyamino linker group. The molecular formula for pegaptanib is: C294H342F13N107Na28O188P28[C2H4O]n (where n is ~900 PEG units, composed of 2 PEG straight chains, each ~450 units in length, with a total molecular weight of ~40 kDa). The total the molecular weight for pegaptanib is ~50 kDa. Pegaptanib has a negative charge of 28, and is thought to have a hairpin structure.

Pegaptanib is an aptamer, an oligonucleotide designed to specifically bind a portion of a molecular target (other than another polynucleotide), much like an antibody. It is not an antisense drug, and is not complementary and does not bind DNA or RNA sequences. Pegap-tanib was designed to potently bind vascular endotelial growth factor (VEGF). Thus, pegaptanib and Macugen are often referred to as anti-VEGF aptamer. Through its binding selectively to VEGF-165, a particular isoform of VEGF, pegatanib blocks VEGF-mediated angiogenesis or neovascularization, including the formation of new blood vessels associated with macular degeneration, a disease of the eye in which blood vessel growth on the retina degrades vision.

Pegaptanib sodium is fully synthetic. It and Macugen may be classed as either not being a biopharmaceutical (based on it being synthetic), or as a borderline or gray area biopharmaceutical (based on it being an RNA sequence mimicking an antibody). Some of the nucleotide units of pegaptanib are not natural, e.g., are fluorinated.

Macugen is supplied in a single-dose, prefilled syringe, two in a package, for intravitreous injection (into the vitreous humor, the gel that fills the eye). It is formulated as a 3.47 mg/mL solution, measured as the free acid form of the oligonucleotide. The active component is 0.3 mg of the free acid form of the oligonucleotide without polyethylene glycol, in a 90 µL deliverable volume. This dose is equivalent to 1.6 mg of pegaptanib sodium (pegylated oligonucleotide) or 0.32 mg when expressed as the sodium salt form of the oligonucleotide moiety. The product is a preservative-free solution containing sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, hydrochloric acid and/or sodium hydroxide to adjust the pH, and Water for Injection, with an osmolality of 280-360 mOsm/Kg, and a pH of 6–7.

Nomenclature: VEGF apatamer [BIO]; Macugen [TR assigned to Eyetech]; pegaptanib sodium [FDA USAN]; pegaptanib octasodium [SY]; RNA, ((2'-deoxy-2'-flu-o-ro)-C-Gm-Gm-AA-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-Am-Gm-(2'-deoxy-2¢-fluoro)U-Gm-Am-Am-(2'-deoxy-2'-fluoro)U-Gm-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-Gm-(3'Æ3')-dT), 5'-ester with a,a'-[4,12-dioxo-6-[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3,13-dioxa-5,11-diaza-1,15-pentadecanediyl]bis[wmethoxypoly(oxy-1,2-ethanediyl)], sodium salt [‘a's are Greek letter alpha; ‘m' is subscripted] [CAS from Prod. insert]; 5'-ester of (2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-Am-Gm-(2'-deoxy-2'-fluoro)-U-Gm-Am-Am-(2'-deoxy-2'-fluoro)U-Gm-(2'-deoxy-2'-fluoro)-C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-Gm-(3'--3')-dT with [[(1S)-1-[[5-(phosphonooxy)pentyl]car-bamoyl]pentane-1,5-diyl]bis(iminocarbonyl)]bis[-methoxy-poly(oxyethane-1,2-diyl)] octacosasodium salt [CAS]; 250689-71-5 [other CAS RN]; 222716-86-1 [CAS RN]; EYE-001 [SY]; NX1838 [SY]; anti-VEGF apatamer [SY]; NX-1838 [SY]; NDC 68782-001-01 [NDC]

Biological.: Pegaptanib potently binds to VEGF-165,the 165 amino acid isoform of VEGF, with a Kd of ~50 pM, and inhibits interaction of VEGF-165 with its cellular receptors — fms-like tyrosine kinase (FLT)-1 and kinase insert domain-containing region (KDR). VEGF-165-specific inhibition is comparable to that achieved with VEGF monoclonal antibodies.

A potential disadvantage of aptamers and other oligonucleotides as drugs is that they are sensitive to nuclease digestion and relatively unstable in vivo. Pegaptanib was selected for its nuclease resistance as part of its discovery/isolation using the SELEX process (discussed below). The carbohydrate (sugar) rings of many of its ribonucleotide bases are modified at the 2’-prime position with a fluorine moiety, and purines are modified with an O-methyl group, except for two unmodified adenosine bases. O-methylation increases affinity for VEGF by 17-fold. Stability is further enhanced by a deoxythymidine at the 3’-terminus linked via a 3’-3’ linkage, and attachment (pegylation) of 40 kDa of a polyethylene glycol (PEG) polymer chain. Pegylation further increases solubility and in vivo half-life, e.g., by wrapping around the molecule and sterically protecting it from enzyme attack and decreasing immunogenicity.

Aptamers are chemically synthesized short strands of RNA (oligonucleotides) that adopt highly specific three-dimensional conformations, and in some respects can act like proteins/antibodies. Aptamer is derived from Greek, with ‘aptus’ meaning to fit, and ‘meros’ meaning part of region. Like antibodies, apatamers can bind with high affinity to target molecules including proteins. Binding relies on the specific 3-dimensional conformation and distributed charges of the properly folded aptamer, and is not dependent on Watson/Crick base pairing or triple helix binding (to another polynucleotide). Aptamers general do not trigger adverse immune responses. To date, no meaningful clinical immunologic reactions to Macugen have been reported.

Over 1 x 1016 different aptamers can be synthesized in small amounts in a single test tube using the SELEX process, and subsequently rapidly screening for binding activity. SELEX (Systematic Evolution of Ligands of Exponential enrichment) is a combinatorial chemistry methodology in which vast numbers of oligonucleotides are screened rapidly for specific sequences that have appropriate binding affinities and specificities toward any target. Thus, novel molecules can be created and screened that either mimic or prevent specific molecules from binding to their receptors, much like antibodies.

Aptamers generally have properties including binding affinity in low nanomolar to picomolar range (similar to antibodies); their selection is entirely chemistry-based; they are more temperature-stable than antibodies return to their original conformation after heating; and are stable with unlimited shelf life; are nonimmunogenic. Aptamers can, theoretically, be targeted to any protein. They offer increased uniformity, in many respects, compared to antibodies, and pharmacokinetic properties can be adjusted by chemical modifications.

Vascular endothelial growth factor (VEGF; originally known as vascular permeability factor) is a secreted 34-43 kDa (predominant species at about 45 kDa) dimeric (homodimer or 2 identical chains), disulfide-linked glycoprotein expressed by a variety of tumor and normal cells. VEGF is an endothelial cell-specific mitogen. VEGF expression is stimulated by hypoxia (low oxygen levels), and is required for tumor angiogenesis or induction of growth of new blood vessels. Cultured human retinal cells, e.g., pigment epithelial cells and pericytes, have been shown to secrete VEGF and to increase VEGF gene expression in response to hypoxia. VEGF appears to play a major role in pathological states/processes related to angiogenesis/neovascularization. Regulation of VEGF expression is potentially useful in treatment or prevention of diseases associated with hypoxia and neovascularization.

Neovascularization or angiogenesis is the process in which sprouting new blood vessels are formed from existing endothelium in response to external stimuli that signal inadequate blood supply (e.g., hypoxia). Angiogenesis is generally rare under normal physiological conditions, but frequently accompanies pathological conditions such as psoriasis, rheumatoid arthritis, hemangioma, and solid tumor growth and metastasis. Angiogenesis is tightly controlled in healthy adults by opposing effects of positive and negative regulators. Under certain pathological conditions, including proliferative retinopathies, rheumatoid arthritis, psoriasis and cancer, positive regulators prevail and angiogenesis contributes to disease progression (see Folkman, et al., Nature Medicine. 1:27-31). In cancer, the notion that angiogenesis is the rate limiting step of tumor growth and metastasis is supported by considerable experimental evidence, and the quantity of blood vessels in tumor tissue is a strong negative prognostic indicator. Growth factors capable of inducing angiogenesis in vivo include acidic and basic fibroblast growth factors, transforming growth factors alpha and beta, platelet derived growth factor (PDGF; see related entries), angiogenin, interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF).

A number of angiogenic growth factors are known, among which VEGF appears to play a key role as a positive regulator of physiological and pathological angiogenesis. VEGF is selectively stimulates endothelial cells to proliferate, migrate, and produce matrix-degrading enzymes, all of which are processes required for the formation of new vessels. VEGF selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD). In addition to being the only known endothelial cell specific mitogen, VEGF is unique among angiogenic growth factors in its ability to induce a transient increase in blood vessel permeability to macromolecules (hence its original and alternative name, vascular permeability factor, VPF). Increased vascular permeability and the resulting deposition of plasma proteins in the extravascular space assists new blood vessel formation by providing a provisional matrix for the migration of endothelial cells. Hyperpermeability is a characteristic feature of new vessels, including those associated with tumors. Compensatory angiogenesis induced by tissue hypoxia is mediated by VEGF.

VEGF is a very potent inducer of blood vessel permeability. In animal tests, VEGF has been shown to be 50,000 times more potent than histamine, the molecule commonly associated with blood vessel leakage related to allergies. Also in animal tests, it has been shown that VEGF is required for the blood vessel permeability associated with wet AMD and diabetic retinopathy.

VEGF occurs in four forms (VEGF-121, VEGF-165, VEGF-189, VEGF-206) as a result of alternative splicing of the VEGF gene. The two smaller forms are diffusible, while the larger two forms remain predominantly localized to the cell membrane as a consequence of their high affinity for heparin. VEGF-165 also binds to heparin and is the most abundant form. Pegaptanib binds in vitro to the major pathological VEGF isoform, extracellular VEGF-165, thereby inhibiting VEGF-165 binding to its VEGF receptors, thus, inhibiting angiogenesis (neovascularization).

The biological effects of VEGF are mediated by two tyrosine kinase receptors (Flt-1 and Flk-1/KDR) whose expression is highly restricted to cells of endothelial origin. While the expression of both functional receptors is required for high affinity binding, the chemotactic and mitogenic signaling in endothelial cells appears to occur primarily through the KDR receptor. The importance of VEGF and VEGF receptors for the development of blood vessels has been demonstrated in mice lacking a single allele for the VEGF gene or both alleles of the Flt-1. In each case, distinct abnormalities in vessel formation were observed. VEGF is produced and secreted in varying amounts by virtually all tumor cells, and tumor metastases are dramatically reduced by VEGF antagonists.

VEGF inhibitors may be useful in a wide variety of proliferative diseases characterized by excessive angiogenesis, e.g., macular degeneration, involving progressive choroidal angiogenesis beneath the macula (a part of the retina responsible for the highest visual acuity), interfering with vision. The stimuli that initiate blood vessel growth in macular degeneration are not known, but VEGF appears to be a key angiogenesis inducer. Inhibitors of VEGF, e.g., pegaptanib, may be useful in attenuating angiogenesis in macular degeneration.

The retina covers the backplane of the eyeball and consists of light receptors and nerve cells that react to light focused on the retina by the lens and cornea. Light falls on the photoreceptors of the retina, called rods and cones, and is converted into electrical signals which travel via the optic nerve to the brain. The central most portion of the retina is the macula, which is the region responsible for seeing color and the acute central vision necessary for activities such as reading, face recognition, watching television and driving.

VEGF is naturally expressed in the retinal pigment epithelium (RPE), which is part of the retina. Early in the course of neovascular age-related macular degeneration (AMD), a combination of factors is thought to stimulate the overexpression of pathologic VEGF in the RPE and surrounding cells. In neovascular (“wet”) AMD, new vessel formation in the retina, consisting largely of defective and leaky vessels, is a key step in this disease, the leading cause of blindness in patients over 50 in Western countries. Once VEGF is overexpressed, it binds to vascular endothelial cells, promoting angiogenesis and increased vascular permeability (leakage) –- two hallmarks of wet AMD.

By preventing blood vessel leakage as well as abnormal blood vessel growth, Macugen offers a two-pronged approach to the treatment of wet AMD. By preventing blood vessel leakage, Macugen also offers a potential treatment for diabetic macular edema (DME), where fluid accumulates in the macula.

In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in animals and humans.

Carcinogenicity studies with pegaptanib have not been conducted, but will likely be required for development and approval of Macugen for diabetic macular edema (DME), which affects patients at a earlier age than AMD, which primarily affects older persons. Pegaptanib and its monomer component nucleotides (2’-MA, 2’-MG, 2’-FU, 2’-FC) were evaluated for genotoxicity and mutagenicity in a battery of in vitro and in vivo assay systems. Pegaptanib, 2’-O-methyladenosine (2’-MA), and 2’-O-methylguanosine (2’-MG) were negative in all assays. 2’-Fluorouridine (2’-FU) and 2’-fluorocytidine (2’-FC) were nonclastogenic and were negative in all S. typhimurium (mutagenicity testing) strains, but produced a non-dose related increase in revertant frequency in a single E. coli tester strain. Pegaptanib, 2’-FU, and 2’-FC tested negative in cell transformation assays. There have been no studies in pregnant women.

Companies.: NeXstar Pharmaceuticals, Inc. (Boulder, CO) originally developed the SELEX process for aptamer generation and selection, and pegaptanib. Gilead Sciences, Inc. acquired NeXstar in 1999 through an exchange of company stock valued at about $550 million. Gilead conducted Phase II trials with pegaptanib for age-related macular degeneration (AMD), diabetic retinopathy (DME), and cancer.

In March 2000, Eyetech Pharmaceuticals, Inc. exclusively licensed worldwide rights from Gilead Sciences for Macugen for all therapeutic indications:. Subject to a right of first negotiation with Gilead for a limited set of indications:, Eyetech has the right to grant sublicenses. Eyetech’s royalty obligations extend on a country-by-country basis until either ten years after the first commercial sale of Macugen or the expiration of the last-to-expire patent licensed from Gilead in each particular country. Eyetech paid a $7 million upfront licensing fee, with Gilead receiving up to $25 million in milestone payments during development, Eyetech being responsible for all R&D and approvals, and Gilead receiving undisclosed royalties on sales. Eyetech also granted Gilead a warrant to purchase 833,333 shares of stock over five years at a fixed price. Gilead provides fill and finish services for Macugen (discussed below).

In Nov. 2006, OSI Pharmaceuticals, Inc. completed acquisition of Eyetech for ~$935 million. With Macugen being Eyetech’s primary asset, the acquisition by OSI was controversial with some concerned about competition from Lucentis (see related entry) from Genentech.

In Dec. 1998, Gilead sold (exclusively licensed) all of its antisense and other oligonucleotide chemistry-related patents to Isis Pharmaceuticals, Inc. In Jan. 2001, Eyetech licensed certain rights to Isis’ broad oligonucleotide, including aptamer, patent portfolio. This was considered essential for pegaptanib manufacture. In Dec. 2004, Isis received a $3 million milestone payment from Eyetech, triggered by the product’s FDA approval. Isis will receive additional milestone payments and royalties on sales. Isis reportedly receives single-digit royalties on sales.

In Dec. 2002, Eyetech entered into a collaboration with Pfizer, Inc. to jointly complete the development of Macugen and co-promote Macugen in the U.S. Eyetech granted Pfizer exclusive rights to develop and commercialize Macugen outside the U.S., and Eyetech will receive royalties on Pfizer’s foreign sales. Eyetech is also entitled to participate in Pfizer’s U.S. detailing of Xalatan, a drug for treatment of glaucoma. Pfizer and Eyetech co-promote Macugen in the U.S. and share related profits, with Eyetech having the right to book all U.S. product sales. This agreement lasts 15 years from the launch of Macugen. Pfizer is potentially obligated to pay Eyetech up to $195.5 million in milestone payments, based on the achievement of worldwide regulatory submissions and approvals; and is potentially obligated to pay Eyetech up to $450 million in milestone payments based upon attainment of agreed upon sales levels of Macugen. In Feb. 2003, Pfizer paid Eyetech $100 million – a $75 million initial license fee and a $25 million equity investment. Pfizer purchased an additional $10 million of common stock at the closing of Eyetech’s initial public offering (IPO) in Feb. 2004. Pfizer funds a majority of Macugen’s ongoing development costs, and is obligated to pay Eyetech a per detail (sales visit) fee for its details to general ophthalmologists and a percentage of incremental net revenues that are above a baseline threshold for its details to retinal specialists.

In Feb. 2002, Eyetech entered into a license, manufacturing and supply agreement with Nektar Therapeutics, Inc. (formerly Shearwater Corp. and Inhale Therapeutic Systems, Inc.) relating to the PEGylation of Macugen. Nektar supplies the PEG reagent used to form pegaptanib. Through this licensing, Enzon Pharmaceuticals, Inc. receives royalties from sales of Macugen from its licensing of straight-chain (non-branched PEG) pegylation technology to Nektar. As further discussed in the PEG-Intron entry, Enzon and Nektar Therapeutics formed a strategic alliance in 2002, with Nektar exclusively offering sublicenses to Enzon’s pegylation technology, with Enzon receiving royalties from related product sales or profits. The agreement expires upon the expiration of the last-to-expire patent licensed from Nektar.

Under its agreements with Gilead, Nektar (Enzon) and Isis, Eyetech is obligated to make payments up to $36.3 million upon achieving specified development and regulatory milestones and to pay royalties based on net sales.

Eyetech uses three distributors in the U.S. — McKesson Specialty, Priority Healthcare and Besse Medical. These distributors ship Macugen to retinal specialists within 24-48 hours of receiving an order.

In Dec. 2004, Isis sold a portion of its Macugen royalty rights to Drug Royalty Corp. Inc. for $24 million over the next three years. Essentially, Isis is foregoing its royalties on the first $500 million of annual Macugen sales through 2009, which now go to Drug Royalty. Royalties on sales of $500 million-$1 billion will be shared equally, and Isis will get 90% of the royalties if the drug sells above $1 billion. After 2009, Isis retains all royalties to Macugen. In Oct. 2005, Isis received $7 million from Drug Royalty as partial payment.

Raylo Chemicals Inc., originally a subsidiary of Degussa AG, is (and has been) the contract manufacturer of pegaptanib sodium lyophilized powder, both for clinical supplies and commercialization . Raylo received a minimum monthly fee of ~$0.6 million until the manufacturing process was validated, after which, the purchase price is calculated on a cost-based formula that adjusts over time depending on a variety of factors. Eyetech also reimburses Raylo for royalties payable to an unspecified third party for patent licensing related to the manufacturing process. Eyetech increased manufacturing capacity by installing additional manufacturing lines at Raylo. As discussed below, Eyetech is also developing its own backup manufacturing facility.

In June 2006, Gilead Sciences initiated acquisition of Raylo Chemicals from Degussa AG.

Eyetech has contracted with Gilead Sciences for formulation of pegaptanib sodium powder into solution (Macugen) and filling of syringes. In Dec. 2003, this agreement was extended to cover fill and finish services for commercial supplies. The price of these services is based on fixed batch and per-unit charges that vary depending on annual order volumes and additional costs that depend on costs of materials procured from third parties and Gilead’s other costs. The term of the agreement runs through the third anniversary of the launch of Macugen in the U.S.

In Nov. 2004, Eyetech acquired a majority interest in Transgenomic, Inc., including its oligonucleotide manufacturing facility in Boulder, CO. The purchase price was $3.0 million in cash, plus the assumption of certain equipment and facilities leases associated with the facility. The facility provided contract manufacturing services for preclinical and clinical nucleic acid-based products. Eyetech plans to invest in this manufacturing facility in Boulder to prepare it as a second-source for commercial scale manufacture of pegaptanib.

Eyetech originally collaborated with Iomed, Inc. (Salt Lake City, UT), using its OcuPhor System for delivery of pegaptanib, prior to selecting pegylation from Nektar Therapeutics, Inc.

In Nov. 2006, it was reported that OSI was seeking to divest Eyetech, with the company providing insufficient sales/profit, particularly since the launch of Lucentis for AMD (see related entry, #279).

In April 2010, Avecia Biotechnology (now Fuji Diosynth) has entered an agreement with Pfizer for the commercial supply of pegaptanib sodium.

In Sept. 2011, Pfizer announced a $200 million expansion of its Grange Castle, Ireland, manufacturing facility, including a new pegylation production facility for Macugen and Somavert.

In Feb. 2012, Valeant Pharmaceuticals International, Inc. acquired Eyetech, including Macugen. reportedly "for an upfront payment and potential future milestones that total significantly less than two times sales."

Manufacture: The manufacturing process for pegaptanib consists of chemical synthesis of the oligonucleotide, purification, PEGylation, further purification, and lyophilization (freeze drying) to form a powder. Each of these steps involves relatively common chemical processes. The chemical synthesis uses conventional oligonucleotide synthesis. Straight-chain pegylation technology is discussed in the PEG-Intron entry (#208).

FDA class: Drug NDA

Approvals: Date = 20041217; original NDA

Date = 20051117; NDA supplement; Indication = approval of a new embossed syringe and revised labeling

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

Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration.

Status: Eyetech submitted the NDA on June 17, 2004, and it was accepted Aug. 1, 2004. The NDA was for wet AMD and diabetic macular edema (DME), and received fast track designation. The Dermatologic & Ophthalmic Drugs Advisory Committee, FDA, considered Macugen on Aug. 27, 2004. A formal vote regarding approval was not taken by the committee.

On Dec. 17, 2004, FDA approved Macugen for the treatment of neovascular AMD. Macugen was launched in Jan. 30, 2005. Until then, the only FDA-approved treatment was for the predominantly classic or dry subtype of neovascular AMD. Although not required for its AMD indication, which primarily affects older persons, because patients with DME tend to be younger than those with wet AMD, FDA will require Eyetech to satisfactorily complete carcinogenicity testing of Macugen prior to its approval for treatment of DME.

On May 5, 2005, Macugen received approval in Canada for the treatment of subfoveal choroidal neovascularization (CNV) secondary to neovascular age- related macular degeneration (neovascular AMD).

On Feb. 2, 2006, the European Union approved Macugen for the treatment of neovascular (wet) age-related macular degeneration (AMD).

In early April 2006, Pfizer and OSI issued a “Dear Healthcare” letter to U.S. healthcare professionals warning that Macugen can cause anaphylaxis/anaphylactoid reactions, including angioedema, following intravitreal administration.

In June 2010, Pfizer submitted an application to extend the EU approval for Macugen to include the treatment of visual impairment due to diabetic macular oedema in the indication. At the time of withdrawal, the application was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP). In July 2011, Pfizer withdraw its application based on the CHMP’s view that the data provided did not allow the Committee to conclude on a positive benefit-risk balance in the applied for indication.

Tech. transfer: Eyetech reported in 2004 it has received or licensed 25 U.S. patents and 22 U.S. applications, and foreign counterparts. These include claims covering the composition of matter and methods of manufacturing and use of Macugen; the composition of matter and method of manufacturing of both modified and unmodified aptamers in general and modified and unmodified VEGF aptamers in particular; and patent applications covering various aspects of ophthalmic drug delivery. Patents licensed from Gilead consist of 14 U.S. patents that expire between 2010-2017 and counterpart filings in other countries. Patents licensed from Nektar consist of nine U.S. patents that expire between 2013 and 2016 and foreign counterpart filings. Patents licensed from Isis consist of two U.S. patents that expire in 2010 and 2014 and foreign counterparts.

U.S. patents licensed from Gilead include:

a) 5,859,228 and 6,168,778 (both originally assigned to NeXtar Pharm.) and 6,426,335 (assigned to Gilead), “Vascular endothelial growth factor (VEGF) nucleic acid ligand complexes.” The later two patents include methods for preparing high affinity 2’-fluoropyrimidine RNA-based VEGF nucleic acid ligands with phosphorothioate internucleoside linkages (e.g., pegaptanib) complexed (covalently bound) with a non-immunogenic, high molecular weight compound (e.g., methyl polyethylene glycol).

b) 6,696,252 and 6,762,290, “High affinity vascular endothelial growth factor (VEGF) receptor nucleic acid ligands and inhibitors, July 13, 2004. U.S. 6,762,290 has only one claim - “1. A purified and isolated non-naturally occurring RNA nucleic acid ligand to VEGFR2 wherein said ligand is selected from the group consisting of the sequences set forth in SEQ ID NO:2 to SEQ ID NO:36,” with one of these presumably pegaptanib. U.S. 6,696,252 claims a variety of VEGF aptamers.

c) The SELEX method is covered by a number of NeXstar (now Gilead) patents including 5,683,867; 6,168,778 and 6,261,774

d) U.S. 6,147,204, "Nucleic acid ligand complexes,' and 6,426,335, "Vascular endothelial growth factor (VEGF) nucleic acid ligand complexes," now assigned to Eyetech Inc., covering aspects of Macugen (but have expired).

Isis reports that its licensed patents concern generic oligonucleotide manufacturing (synthesis) technology, not Macugen’s composition of matter, formulation or use.

Pegylation technology licensed by Eyetech was originally developed by Shearwater Corp., now Nektar nhale Therapeutic Systems, Inc., a subsidiary of Inhale Therapeutic Systems, Inc. See the Pegasys entry for further background about PEGylation technology.

In July 2006, the University of Alabama (Huntsville, AL; UAH) settled a patent dispute brought against Nektar and its original founder, Dr. Milton Harris, formerly with the university through a cash payment of $25 million. Nektar and Dr. Harris jointly made an upfront payment totaling $15 million to UAH; and Nektar will pay UAH $1 million/year for ten years. UAH dismissed all claims related to the Nektar’s PEGylation patent portfolio and Nektar dismissed all counterclaims. UAH had sued Nektar in U.S. District Court for patent infringement, breach of contract license, violation of the Alabama Trade Secrets Act and unjust enrichment. Dr. Harris and another researcher developed a PEGylation technology, which was patented by UAH (U.S. 5,252,714, “Preparation and use of polyethylene glycol propionaldehyde “). The university had entered into a royalty agreement with Dr, Harris for products developed from this discovery, and Harris created Shearwater Polymers, now Nektar. UAH claimed that Harris, without UAH’s knowledge, made a number of other discoveries related to the PEG technology in the following years, patented 28 of them, that Harris was required to notify UAH of any discovery related to the original PEG patent, and that the patents were “obvious derivatives” of and “equivalent” to the original UAH PEG patent.

Trials: Eyetech began Phase I trials in Aug. 1998. Pegatanib was the first aptamer ever to enter U.S. clinical trials.

Two Phase II/III pivotal trials (Study EOP1003 and Study EOP1004) for wet AMD were initiated in 2nd half 2001 and were underway in Dec. 2002 when Eyetech concluded its agreement with Pfizer. One of these trials was in North America and enrolled 578 patients. A total of 117 retinal specialists at 117 centers participated in the pivotal trials. Patients were randomized to receive control (sham treatment) or 0.3 mg, 1 mg or 3 mg Macugen administered as intravitreous injections every 6 weeks for 48 weeks. A total of ~1,200 patients were enrolled with 892 patients receiving Macugen and 298 receiving a sham injection. Enrollment criteria were designed to assess Macugen in a broad patient population. Both trials enrolled patients with subfoveal wet AMD of all three lesion subtypes, with a wide range of lesion sizes and with a variety of other lesion characteristics. The median age of the patients was 77 years. The two trials enrolled patients with neovascular AMD characteristics including classic, occult, and mixed lesions of up to 12 disc areas and baseline visual acuity in the study eye between 20/40 and 20/320. Patients received a mean 8.5 treatments out of a possible 9 total treatments across all treatment arms. At the end of the first year (week 54), approximately 1,050 of the original 1,200 patients were rerandomized to either continue the same treatment or to discontinue treatment through week 102. Patients who continued treatment in year 2 received a mean of 16 treatments out of a possible total 17 overall. The primary efficacy endpoint was the proportion of patients losing less than 15 letters of visual acuity, from baseline at up to 54 week assessment (the same as for the pivotal trials for Visudyne). Verteporfin photodynamic therapy (PDT; Visudyne) usage was permitted at the discretion of the investigators in patients with predominantly classic lesions.

Based on the combined patient populations of both trials, the primary efficacy endpoint was met with statistical significance for all three doses of Macugen used. The 0.3 mg dose was the lowest effective dose. On a combined basis, 70% of the patients treated with the 0.3 mg dose of Macugen lost fewer than 15 letters of visual acuity at 54 weeks compared to 55% of the patients in the usual care control group, resulting in a relative difference of 27% between the treated and the control groups. Each of the three dose levels tested had a favorable safety profile. For the 0.3 mg Macugen dose, the primary endpoint was achieved with statistical significance in both the N. American and international trials using more stringent Hochberg statistical methodology. The p-value was 0.003 in the N. American trial and 0.011 in the international trial. The treatment effect of Macugen was consistent across all three subtypes of subfoveal wet AMD with respect to both mean vision loss and prevention of three line loss. PDT (Visudyne) overall use was low. Macugen was less effective during the second year than during the first year. The safety and efficacy of Macugen therapy beyond 2 years and administered to both eyes concurrently has not been studied.

Results from the VEGF Inhibition Study in Ocular Neovascularization (VISION) study were reported in the Dec. 30, 2004 New England Journal of Medicine. Among patients receiving 0.3 mg Macugen, 70% lost less than three lines of vision on the study eye chart after 54 weeks, compared with 55% of patients in the control group (p < 0.001). The results were consistent regardless of disease subtype and lesion size. Macugen reduced the risk of progression to legal blindness in the treated eye by half at the end of one year (38% of patients in the 0.3 mg group vs. 56% in the sham group; p < 0.001).

In May 2005, preliminary results were reported from a Phase II study of Macugen in diabetic macular edema (DME), with Macugen reversing capillary microaneurysms, retinal ischemia and neovascularization – important signs of diabetic retinopathy.

In Oct. 2005, further analysis of the outcomes of patients with early exudative lesions in the VISION study showed that at week 54, 76% of patients in group 1 receiving pegaptanib lost fewer than 15 letters or three lines of vision on the ETDRS eye chart, compared with 50% of patients undergoing usual care. In group 2, that proportion was 80% and 57%, respectively. A number of patients treated with pegaptanib even regained some sight. Patients who underwent usual care for AMD were 10 times more likely to experience severe vision loss than those treated with pegaptanib. A follow-up, prospective, open-label, multi-center trial to evaluate the efficacy and safety of pegaptanib in 40 patients with early onset of AMD was initiated in Oct. 2005.

In Oct. 2005, Eyetech initiated a double-blind, placebo-controlled international Phase III trial in 900 patients who receive intravitreous injections of 0.3, 0.03, or 0.003 mg of Macugen, or sham injections, every 6 weeks for 3 years.

In June 2006, positive results were reported from a Phase II trial of Macugen for treatment of central retinal vein occlusion. More than 90% of patients with the condition experienced visual improvement at 30 weeks, vs. 69% in the placebo control arm. Overall, the Macugen group saw a benefit to their visual acuity, with 7.5 letters improvement (on the vision chart) among low-dose 0.3 mg receivers and 10.2 letters improvement in the higher dose 1 mg cohort. This compared to a loss of 1.9 letters over 30 weeks among placebo recipients. Vision gain was seen with a single injection of Macugen within six weeks’ treatment, compared to a loss in the control group. This may boost Macugen off-label use for this indication.

In June 2006, OSI and Pfizer initiated LEVEL (EvaLuation of Efficacy and safety in maintaining Visual acuity with sEquential treatment of neovascuLar AMD), a Phase IV trial of the safety and efficacy of Macugen as a maintenance therapy for patients who have received prior neovascular AMD treatment, particularly off-label use of Avastin (bevacizumab; see related entry #275) from Genentech, and experienced improvement in macular disease. The 54-week trial is enrolling 1,000 patients at 100 sites in the U.S. The primary endpoint is the percentage of subjects who remain at baseline vision or gain (greater than or equal to 0 lines) vision from baseline to 54 weeks. Secondary endpoints include the percentage of subjects maintaining or gaining one, two and three lines of visual acuity at week 54 compared to pre-enrollment baseline vision (treatment initiation baseline); the mean change of visual acuity from baseline to Week 54; the percentage of subjects losing less than three lines of vision at 54 weeks; and anatomical outcomes on fluorescein angiography and optical coherence tomography.

In spring 2007, despite OSI seeking to divest Eyetech and Macugen, OSI and Pfizer were continuing the LEVEL induction maintenance study in AMD. A Pfizer/EyeTech-planned trial to study Macugen for diabetic macular edema was ongoing, but on a smaller scale than originally planned. The trial will now be a 300-patient, two-year trial, rather than a 900-patient, three-year trial. In summer 2007, as recommended (required) by EU authorities, Macugen started a new European Phase III trial, AGENDA, of Genasense plus dacarbazine for treatment of patients with advanced melanoma.

Disease: Age-Related Macular Degeneration (AMD) is a chronic progressive disease of the macula that results in the loss of central vision. The most common symptoms are a central blurred or blank spot, distortion of objects or simply blurred vision. Peripheral vision usually remains intact. The disease typically affects patients initially in one eye, with a high likelihood of it occurring in the second eye over time. Because AMD is strongly correlated with aging, it is likely to recur as aging continues, and treated patients often require retreatment.

AMD is the leading cause of severe vision loss and blindness in patients over the age of 50 in the developed world. According to the Macula Vision Research Foundation, as many as 15 million people in the U.S. suffer from some form of AMD, with more than 1.6 million experiencing the active blood vessel growth and blood vessel leakage associated with wet AMD, the type for which Macugen is approved. AMD Alliance International reports ~200,000 new cases of wet AMD arise each year in the U.S. According to the Centers for Disease Control and Prevention (CDC), the rate of AMD increases sharply with age, from 18% among people 70-74 years of age to 47% among people 85 years and older. According to the U.S. census bureau, the number of people in the U.S. aged 50 or older is ~80 million, and will increase by ~40% over the next two decades.

Dry AMD is the most common form, representing ~90% of all AMD cases. However, dry AMD accounts for only 10% of the severe vision loss associated with AMD. Over time, dry AMD often develops into wet AMD.

Wet AMD represents ~10% of all cases of AMD, but is responsible for 90% of the severe vision loss associated with AMD. Wet AMD occurs when new blood vessels from the tissue layer in the eye just beneath the retina, called the choroid, invade into the retinal layers through a membrane known as Bruch’s membrane. This abnormal blood vessel growth (angiogenesis) is called choroidal neovascularization. These new blood vessels tend to be fragile and often bleed and leak fluid into the macula, resulting in loss of vision. Untreated, this blood vessel growth and leakage can lead to scarring and, eventually, to the destruction of the macula. The majority of patients with wet AMD experience severe vision loss in the affected eye within months to two years after diagnosis of the disease. Wet AMD that occurs directly under the fovea is known as subfoveal wet AMD. The abnormal blood vessel growth of wet AMD can be located either directly under the area at the center of the macula, known as the fovea, or away from the fovea. The fovea is responsible for the ability to see fine detail and color. Wet AMD that occurs elsewhere in the macula is known as either extrafoveal or juxtafoveal wet AMD. More than 90% of wet AMD cases are subfoveal. Subfoveal wet AMD is divided into three principal subtypes based on the pattern of the abnormal blood vessels, or lesions, as seen in the retina through an imaging procedure known as angiography. The classic pattern consists of well-defined abnormal blood vessels with distinct edges. In the occult pattern, the edges of the abnormal blood vessels are more poorly demarcated and diffuse.

Market: Total 2006 sales in the first three quarters were $96, equivalent to $128 million/year. Total 2005 sales of Macugen were $185 million.

With the acquisition of Eyetech by OSI, various analysts projected Macugen sales to peak in 2006 at about $300-$325 million, with sales likely peaking in 2006 due to competition from Lucentis. However, sales of Macugen have significantly declined since the launch of Lucentis from Genentech (see #276) for wet AMD, and off-label use of Avastin (see #275) for AMD could further cut into Macugen sales. U,S. sales of Macugen were just $9 million in 3rd quarter 2006, vs. $59 million for the same period in 2005, while sales of Lucentis were $153 million.

Macugen is reported (3/2007) to have a list price of $995 per injection, with the treatment’s six-week dosing bringing the annual cost on a list price basis to $7,960.

The 2007 Average Wholesale Price (AWP) is $1,194.00/single-dose vial, with a Direct Price (Manufacturer’s disount) of $995.00 (Red Book, 2007).

The potential market size, based on epidemiological data, for Macugen is discussed above in the Medical section. This primarily involves the ≥1.6 million persons in the U.S. with wet AMD.

In March 2005, a study from Pharmacor, Decision Resources, Inc. projected “Macugen will make a big impact in the age-related macular degeneration drug market.” Macugen and new treatments in coming years, combined with a dramatic increase in the drug-treated population, will result in a increase nearly sevenfold from 107,000 AMD patients in 2003 to approximately 750,000 patients in 2013 in the major pharmaceutical markets. “Expansion of the drug-treated patient pool and increasing use of photodynamic therapy [Visudyne] in combination with one or more emerging therapies [e.g., Macugen] will expand the age-related macular degeneration market from US$ 275 million in 2003 to nearly US$ 2.3 billion in 2013.”

Eyetech is in process of establishing its own focused domestic sales and marketing capabilities for Macugen, Xalatan and other ophthalmic products Eyetech estimates there are ~1,400 retinal specialists in the U.S., and plans to target most of its sales and marketing efforts at these specialists in collaboration with Pfizer, which has substantial sales and marketing capabilities. Pfizer has primary responsibility for promoting this product in the U.S. market to general ophthalmologists.

Macugen's cost is covered by Medicare when administered in the physician’s office. CMS also reimburses physicians for administering the product to beneficiaries.

In the U.K., Macugen received approval in May 2006, but the National Institute of Health and Clinical Excellence (NICE) refused to support U.K. National Health Service (NHS) use of Macugen, and delayed finalization of this decision to Aug. 2007. Even though approved in the U.K., only a very small percentage of eligible patients receive Macugen. Some NHS districts only consider treatment once a patient has lost sight in one eye, while many others are waiting for further guidance from NICE.

Competition: Macugen faces serious competion from Lucentis, a recombinant VEGF monoclonal antibody (see related entry in the Recombinant DNA Products section).

In the U.S., prior to Macugen, the only FDA-approved therapy for wet AMD was Verteporfin photodynamic therapy (PDT; Visudyne). This involves a two-step process in which a photodynamic dye is administered systemically by intravenous infusion and then a dose of low energy light is delivered to the target site to activate the photosensitizer and destroy the newly grown abnormal blood vessels. Worldwide sales of Visudyne in 2003 were ~$357 million. Visudyne’s approved indications: cover ~25% of U.S. wet AMD patients and ~65% of European wet AMD patients, leaving a significant unmet medical need (for Macugen). However, the U.S situation changed somewhat in 2004. Visudyne is approved in the U.S. only for the treatment of the predominantly classic subtype of subfoveal wet AMD, and in the European Union only for the treatment of the predominantly classic and occult subtypes of subfoveal wet AMD. In Jan. 2004, the Centers for Medicare & Medicaid Services (CMS) issued a decision stating its intention to expand reimbursement for Visudyne therapy to include coverage for the minimally classic and occult subtypes, but only in situations in which the patient’s lesions are small (less than 4 disc areas) at the time of initial treatment or within three months prior to initial treatment and have shown evidence of progression within the three months prior to initial treatment. This change was implemented in mid-2004.

Thermal laser (photocoagulation) treatments are some-times used for AMD treatment, but these are only effective in a small percentage of patients with well-defined, classic lesions, and in these patients there is about 50% recurrence. Patients frequently develop blind spots, known as scotomas, as a result of laser destruction of the retina.

In Dec. 2004, Alcon Labs. reported disappointing trials and halted development of its AMD drug, Retaane, which had been expected to compete with Macugen.

Ongoing: Macugen is in trials for treatment of diabetic macular edema (DME), which like AMD is a serious diseases of the retina that can lead to severe vision loss and blindness. Pfizer and Eyetech are jointly investigating anti-VEGF treatments in diabetic macular edema and retinal vein occlusion, two other causes of vision loss. Eyetech and Pfizer planned to conduct a pivotal Phase II/III diabetic macular edema trial that will include the diabetic retinopathy score as a pre-specified secondary endpoint, expected to begin in the second half of 2005.

In Jan. 2006, PR Pharmaceuticals, Inc. (PRP) and OSI Pharmaceuticals formed a collaboration for the development of a sustained release formulation of Macugen using PRP’s proprietary ProPhase encapsulation technology. PRP granted OSI an exclusive license to ProPhase for Macugen in the treatment of eye diseases. PRP is responsible for formulation and manufacture for non-clinical and clinical trials. OSI, through its eye disease unit, Eyetech, is responsible for clinical development and has the right to manufacture and commercialize any resulting product.

R&D: Potential competition for Macugen includes Alcon, Inc. developing a steroid for the treatment and prevention of predominantly classic subfoveal wet AMD injected behind the eye using a customized injector inserted around the eye; Miravant Medical Technologies developing a photodynamic therapy that is similar to Visudyne for the treatment of wet AMD; Bausch & Lomb Inc. and Control Delivery Systems, Inc. developing a surgically placed non-erodible intraocular implant for the delivery of steroids to treat DME and swelling resulting from other causes; Allergan, Inc., which recently acquired Oculex Pharmaceuticals, developing a bioerodible steroid implant for the treatment of persistent macular edema; Eli Lilly & Co. developing an orally administered inhibitor of an enzyme, PKC beta, for the treatment of diabetic retinopathy; Regeneron Pharmaceuticals, Inc. and Sanofi Aventis S.A. developing a fusion protein that contains portions of the extracellular domains of two different VEGF receptors (Phase I trials in AMD started in March 2004); and Genaera Corp. developing a small molecule drug derived from the Dogfish shark.