Status - approved; marketed

Organizations involved:

Hoffmann-La Roche Inc. – Manuf.; R&D; Tech.; World mark.

Shearwater Corp. – Tech.; Former

Nektar Therapeutics, Inc. – Manuf. other; Tech.

Inhale Therapeutic Systems, Inc. – Parent

Chugai Pharmaceutical Co. Ltd. – Japan mark.

Enzon, Inc. – Patent dispute; Tech.

Schering-Plough Corp. – Patent dispute

University of Alabama – Tech.; Patent dispute

Valeant Pharmaceuticals, Inc. – Tech.; Patent dispute

Ribapharm, Inc. – Tech.; Patent dispute; Former

ICN Pharmaceuticals – Parent; Former

Weston Medical plc – Tech.

Cross ref.: See the Interferon Products entry in the Blood Products, Human section; the entry above for Interferon alfa-2a (from which this is manufactured); and the entry for another pegylated interferon product, Interferon alfa-2b (PEG-Intron).

Description: Peginterferon alfa-2a (PEGylated-40K interferon alfa-2a; Pegasys) is an aqueous formulation of a pegylated form of recombinant Escherichia coli (E. coli)-expressed interferon alfa-2a (Roferon A) currently marketed by Roche. Pegylation involves the covalent linkage of a synthetic, inert, N-hydroxysuccinimide ester derivative of bis-monomethoxy branched polyethylene glycol (mPEG2-NHS 40 kDa reagent) molecule with a molecular weight of about 40 kDa to the interferon alfa-2a molecule. In addition to the N-terminal lysine of interferon alfa-2a, there are 11 lysines available for pegylation, but pegylation is primarily distributed among four major sites (Lys31, Lys121, Lys131, or Lys134). This PEG moiety is linked to the interferon alfa moiety at a lysine residue on interferon alfa-2a via a stable amide bond. Peginterferon alfa-2a has an approximate molecular weight of 60,000 Daltons (~60 kDa). With a recent approval, Pegasys may be combined with oral ribavirin, a nucleoside analog (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) with a broad spectrum of antiviral activity, for treatment of chronic hepatitis C. Roche has developed its own form of oral ribavirin, Copegus, for use with Pegasys.

The inert PEG strand wraps around and protects the interferon alfa-2a molecule in vivo, substantially increases its in vivo half-life, and decreases immunogenicity by sterically hindering the approach of other molecules. The branched PEG side chain of Pegasys is larger (40 kDa) and confers somewhat different properties than the smaller straight PEG side chain (12 kDa) used with PEG-Intron from Schering-Plough. Roche has claimed that clinical superiority of Pegasys vs. PEG-Intron is linked on its larger and branched side chain.

Pegasys is packaged in single-use vials and prefilled syringes (approved in 2004), singly and in packages of four (monthly convenience pack). Each vial contains approximately 1.2 mL of solution at a concentration of 180 µg/mL to deliver 1.0 mL of interferon alfa-2a by subcutaneous (SC) administration, with injection of 1.0 mL. Each mL contains 180 µg peginterferon alfa-2a, along with 8.0 mg sodium chloride, 0.05 mg polysorbate 80 (Tween 80), 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.05 mg acetic acid. Each syringe contains 0.6 mL at a concentration of 180 µg/0.5 mL to delivery 0.5 mL, 180 µg of peginterferon alfa-2a, along with 4 mg sodium chloride, 0.025 mg polysorbate 80 (Tween 80), benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid, with the solution at pH = 6.0 ± 0.5. Pegasys is stored at 2-8°C (refrigerated). The dating period for Pegasys is 12 months from the date of manufacture, defined as the date of final sterile filtration of the formulated drug product. The dating period for bulk interferon alfa-2a is 18 months when stored frozen at -70˚C.

Nomenclature: Interferon alfa-2a, rDNA, PEG- [BIO]; Pegasys [TR]; peginterferon alfa-2b [FDA INN CAS]; PEGylated-40K interferon [SY used by Roche]; 198153-51-4 [CAS RN]; interferon alpha-2a, recombinant, pegylated [SY]; interferon alfa-2a, recombinant, pegylated [SY]; Ro 25-8310/000 [SY]; NDC 00004-0350-09; NDC 00004-0352-39 [NDC]

Biological.: Peginterferon alfa-2b has biological activity derived from its interferon alpha-2a moiety, the same recombinant interferon in Roferon A also marketed by Roche. In in vitro (cell-based) assays, the activity of a number of pegylated alpha interferons, whose pharmacological effects involve receptor interactions; and activity is inversely proportional to mass of the attached PEG molecule, and is not predictive of in vivo biological activity. In in vivo assays, alpha interferons with a single PEG molecule attached are superior (better distributed throughout the body and more slowly delivered to the liver and spleen) vs. alpha interferons with smaller PEG chains at multiple sites. Relative to nonpegylated and linear PEG alpha interferon conjugates, branched PEG alpha interferon conjugates exhibit increased pH and thermal stability, as well as greater stability toward proteolytic digestion.

Attachment of a PEG stand to the polypeptide backbone of interferon alpha-2a results in some conformational perturbations, which may adversely affect alpha interferon receptor/ligand interactions and lower binding affinity. This is one reason in vitro antiviral activity/potency of peginterferon alfa-2a (Pegasys) is considerably decreased compared to interferon alfa-2a (Roferon A). The in vitro antiviral activity of peginterferon alfa-2a is only 7% of the parent molecule’s activity (while the in vivo antitumor activity is several-fold enhanced compared to interferon alfa-2a). The relatively short incubation time (hours) of the in vitro antiviral assay is insufficient for the lower affinity peginterferon alfa-2a to reach peak activity. In vivo bioassays in mice are much longer (days), and the extended exposure time afforded by the longer half-life of the peginterferon alfa-2a compensates for any loss in binding interaction due to pegylation.

The better physical and thermal stability, greater protection against proteolytic degradation, higher solubility, longer in vivo circulating half-life, and lower clearance of peginterferon alfa-2a result in improved clinical efficacy compared to interferon alfa-2a (Roferon), despite its much lower in vitro antiviral activity. The end-result is maximum biological effect. A sustained release prodrug mechanism for peginterferon alfa-2a has been ruled out, because the amide bond between PEG and interferon alfa-2a remains stable (i.e., the interferon is not released from the conjugate). With Pegasys, the cumulative administration of a smaller amount of the active interferon alfa-2b moiety apparently reduces interferon-associated adverse effects.

The amount of time that a pegylated protein is able to remain intact in the body directly correlates with the size of the PEG strand(s) attached to it. The PEG strand in Pegasys is more than twice as large as the interferon protein. The mean systemic clearance for peginterferon alfa-2a (Pegasys) in healthy subjects is approximately 100-fold lower than that for interferon alfa-2a (Roferon-A). Administration of conventional interferon, e.g., Roferon A, using a standard three-times weekly administration regimen results in peaks and troughs in the blood levels of interferon, while less frequent (once weekly) administration of peginterferon alfa-2a results in more constant and longer-lasting blood levels of interferon. With Pegasys, maximal serum concentrations (Cmax) occur between 72-96 hours post dose, and are sustained for up to 168 hours. The Cmax and AUC measurements of Pegasys increase in a dose-related manner. Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2.0. The mean terminal half-life after subcutaneous dosing in patients with chronic hepatitis C is 80 hours (range 50-140 hours), compared to 5.1 hours (range 3.7-8.5 hours) for Roferon-A.

Companies.: Shearwater Corp., now Nektar Therapeutics, Inc., has been involved in a collaboration with Hoffmann-La Roche Inc. for the development and manufacture of pegylated recombinant interferon. Inhale Therapeutic Systems, Inc. acquired Shearwater in 2001, and renamed the company Nektar Therapeutics, Inc., in Jan. 2003. A PEG reagent, a branched 40K succinimidyl derivative of PEG (mPEG2-NHS 40 kDa reagent; PEG2-NHS), used for further manufacture of peginterferon alfa-2a in manufactured by Shearwater/Nektar.

Hoffmann-La Roche manufactures Pegasys using its own recombinant interferon alpha-2a (see Roferon entry above) and pegylation reagents from Nektar. Roche markets Pegasys in the U.S. and most other countries worldwide. Chugai Pharmaceutical Co. Ltd. markets Pegasys in Japan.

Roche on its own developed Copegus, a generic form of oral ribavirin comparable to previously-approved Rebetol from Schering-Plough (developed and manufactured by Ribapharm/ICN, now Valeant).

Chiron Corp. conducted research with pegylated alpha interferon, but did not pursue commercial development.

Manufacture: Roche had originally used a much smaller 5 kDa PEG chain with an active carbonate group to produce a 5 kDa urethane-linked PEG-interferon alfa-2a. Clinical trials conducted with this conjugate were unsuccessful, with the circulating half-life only slightly improved relative to that of the native protein, and development was halted in 1994 during Phase II trials. Roche then partnered with Shearwater, which provided a second-generation branched 40K succinimidyl derivative of PEG (PEG2-NHS; mPEG2-NHS 40 kDa reagent) for coupling with interferon alfa-2a. The resulting peginterferon alfa-2b (Pegasys) achieved essentially constant blood concentrations (a primary goal for effective therapy) with once-a-week subcutaneous injections in clinical trials. Peginterferon alfa-2b also had decreased clearance relative to native interferon, with an elimination half-life of 77 hours versus 9 hours, and exhibited a low volume of distribution and sustained absorption from the subcutaneous injection site. Roche then sponsored development of peginterferon alfa-2b, initially for treatment of chronic hepatitis C.

See the interferon alfa-2a (Roferon A) entry above for information about manufacture of the alpha interferon component of the peginterferon alfa-2a conjugate. Peginterferon alfa-2a is formed by reaction of an N-hydroxysuccinimide ester derivative of a 40 kDa bis-monomethoxy branched polyethylene glycol (mPEG2-NHS 40 kDa reagent) molecule (obtained from Shearwater/Nektar) with a free lysine amino group of interferon alfa-2a, forming an stable amide bond. Peginterferon alfa-2a is comprised of mono-pegylated interferon alpha-2a (1 PEG chain per interferon alfa-2a).

FDA class: Biologic BLA

CBER class: Biological Response Modifiers

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 20021016; BLA, first approval; Indication = monotherapy use for treatment of chronic hepatitis C

Date = 20021204; BLA supplement; Indication = use in combination with oral ribavirin (Copegus) for treatment of chronic hepatitis C

Date = 20040108; BLA supplement; Indication = approval of prefilled syringes of Pegasys

Date =20040604; BLA supplement; Indication = approval of Pegasys co-packaged with Copegus (ribavirin)

Date =20050225; BLA supplement; Indication = approval of Pegasys in combination with Copegus for treatment of chronic hepatitis C in patients coinfected with hepatitis C and HIV.

Date =20050513; BLA supplement; Indication = approval of Pegasys for treatment of chronic hepatitis B virus (HBV) infection, including HBeAg-positive and -negative HBV

Date = 20050822; BLA supplement; Indication = revision of labeling based on the results of a two year oral (intubation) carcinogenicity study in rats (with toxicokinetics); and revisions to the HOW SUPPLIED AND STORAGE sections of the package insert

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 5/2004]:

PEGASYS, peginterferon alfa-2a, alone or in combination with Copegus, is in indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not been previously treated with interferon alfa. Patients in whom efficacy was demonstrated included patients with compensated cirrhosis and histological evidence of cirrhosis (Child-Pugh class A).

Status: A BLA for once weekly subcutaneous injection for treatment of chronic hepatitis C was submitted on May 22, 2000 (about 1/2 year after Schering-Plough filed for approval of PEG-Intron). The application was accepted for standard review (decision targeted for ≤12 months). In early 2001, Roche received a complete response letter from FDA requestiong further information regarding clinical trials. The letter did not raise any safety or manufacturing issues, and no new clinical trials were required. However, approval of the BLA was delayed. This delay allowed Schering-Plough to receive approval, launch and market PEG-Intron and the combination of PEG-Intron/oral ribavirin (Rebetol) for a period in the U.S. without competition from Roche. The BLA was approved on October 16, 2002; approval time = ~2.15 years)

Pegasys is exempt from CBER/FDA lot release requirements.

In June 2002 (before approval of the original BLA), Roche submitted a BLA supplement for approval of Pegasys plus Copegus (Roche’s own brand of oral ribavirin) for treatment chronic hepatitis C in patients without cirrhosis and with compensated liver disease. FDA granted this application priority (6 months target review) status. On Nov. 14, 2002, the FDA’s Antiviral Drugs Advisory Committee unanimously recommended approval of the combination for treatment of chronic hepatitis C infection, and approval was granted in December.

Pegasys received European Union (EU) approval on June 20, 2002 for treatment of chronic hepatitis C, both as a combination therapy with oral ribavirin and as monotherapy in those intolerant to ribavirin. Pegasys is indicated for the treatment of histologically proven chronic hepatitis C in adult patients, including patients with early stage cirrhosis. In June 2002, Roche also received its first European approval (in the Netherlands) for marketing of Copegus, its own brand of ribavirin (used in combination with Pegasys for even better efficacy for treatment of chronic hepatitis C). approvals for Copegus have been granted by other European countries.

Chugai received approval for Pegasys for chronic hepatitis C in Japan in Oct. 2003, becoming the first pegylated interferon available in Japan.

In July 2004, Roche submitted filed a supplemental BLA for FDA approval of Pegasys (180 µg weekly by subcutaneous injection) for treatment of chronic hepatitis B (not C) infection, as well a MAA for European Union approval. Roche had previously filed for approval in Switzerland, with Swiss approval potentially supporting approval in 80 countries worldwide that base their approvals on Swiss approvals. Roche filed for the treatment of both hepatitis B ‘e’ antigen-positive (HBeAg-positive) and andHBeAg-negative chronic hepatitis B patients based on three trials in 1,545 patients from about 20 countries in which Pegasys showed significant therapeutic benefits over the two current standard therapies, interferon alpha (Roche’s interferon alfa-2a, Roferon-A) and lamivudine (3TC; Epivir-HBV) from GlaxoSmithKline.

On Nov. 11, 2004, the European Union granted supplemental approval for Pegasys treatment of chronic hepatitis C patients with persistently ‘normal’ liver (ALT) enzymes,.about 30% of the chronic hepatitis C population in Europe. Under prior reatment guidelines, hepatitis C patients with normal liver enzymes would not normally have been eligible for treatment.

In late Jan. 2005, the European Union granted supplemental approval for use of Pegasys in combination with Copegus (ribavirin) to treat chronic hepatitis C virus infection in patients co-infected with HIV and normal levels of liver enzymes, based on results from the APRICOT study. FDA granted supplemental approval to the same indiction on Feb. 25, 2005.

On Feb. 5, 2005, the European Union granted approval of Pegasys monotherapy for treatment of chronic hepatitis B virus (HBV) infection, including both HBeAg-positive and negative HBV. This was another major approval that Pegasys received well ahead of PEG-Intron.

On May 13, 2005, FDA granted supplemental approval for Pegasys monotherapy for treatment of chronic hepatitis B virus (HBV) infection. Pegasys has shown efficacy for treatment of both hepatitis B virus e antigen (HBeAg)-positive and HBeAg-negative patients. HBeAg-negative chronic hepatitis B is more prevalent in Mediterranean countries and Eastern Europe, and is more difficult-to-treat and associated with a poorer prognosis. Pegasys has shown superiority to lamivudine (Epivir-HBV) and alpha interferon currently used for chronic hepatitis B. Pegasys had received approval for chronic hepatitis B in the U.S., European Union, Hong Kong, China (PRC), India, New Zealand, Switzerland, Taiwan, and Thailand. Pegasys is the first (and only) pegylated interferon to be indicated for the treatment of chronic hepatitis B.

In Sept. 2005, Teva received FDA approval for its generic version of Copegus (ribavirin). In Oct. 2005, Three Rivers Pharmaceuticals Inc (acquired by Kadmon Pharmaceuticals LLC in fall 2010) received approval for Ribasphere, its version of generic ribavirin. The company share marketing with PAR Pharmaceuticals Inc.

In Jan. 2007, Copegus (ribavirin) was approved in Japan for use in combination with Pegasys for chronic hepatitis C. This was supported by a Japanese Phase III 48-week clinical study, with sustained virological response (SVR) in 59.4% of patients receiving the combination vs, 24.0% for Pegasys monotherapy group.

On March 6, 2007, Pegasys plus Copegus (ribavirin) received supplemental European Union (EU) approval for a shorter treatment duration in chronic hepatitis C genotype 1 and 4 patients showing an initial response to therapy. Early responders can now receive a shortened, 24-week duration of treatment -- half the normal treatment duration. Patients must have either genotype 1 HCV with a low pre-treatment viral load (defined as <800,000 IU/mL) and an undetectable viral load at weeks 4 and 24; or genotype 4 HCV regardless of pre-treatment viral load and an undetectable viral load at weeks 4 and 24. The EU approval was based on data from two pivotal clinical trials for Pegasys plus Copegus showing that among patients who achieved a rapid viral response (undetectable viral load at week 4) in the first month of treatment, up to 93% of patients with genotype 1 HCV with a low pre-treatment viral load and 83% of patients with genotype 4 were cured (undetectable HCV RNA) following only 24 weeks of therapy - a similar cure rate to that seen following 48 weeks of therapy.

In April 2007, Schering-Plough Corp. (now Merck) received approval from the State Food and Drug Administration (SFDA), China (PRC), to market PEG-Intron for the treatment of patients with chronic hepatitis B, the most prevalent infectious disease in China and one of the country’s leading causes of death. It had originally received approval in China in 2004 for treatment of chronic hepatitis C. There are 120 million chronic carriers of the hepatitis B virus in China, and each year more than 330,000 people die due to hepatitis B-related complications, including cirrhosis and liver cancer. However, PEG-Intron will hae to compete against a variety of biogeneric (knock-off) versions of non-peglyalted interferons, including those manufactured in China.

On Dec. 4, 2008, Pegasys plus Copegus (ribavirin) received European Union (EU) approval for the retreatment of hepatitis C patients who were not successfully treated with an initial course of interferon alpha (pegylated or non-pegylated), either alone or in combination with ribavirin.. [However, at least one published study has reported that Pegasys did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis who had not had a response to initial treatment].

Tech. transfer: See the entry above for interferon alfa-2a, rDNA (Roferon A) from Roche for information about interferon alfa-2a patents, licensing and disputes. See also the interferon alfa-2b, rDNA (Intron A) entry for further discussion of interferon patent disputes.

Pegasys is manufactured using a proprietary pegylation process using branched PEG technology and reagents licensed by Hoffmann-La Roche Inc. from Shearwater Polymers, Inc., now Nektar Therapeutics, Inc., a subsidiary of Inhale Therapeutic Systems, Inc. As described in the manufacture section above, a strands of synthetic, inert, branched-chain, polyethylene glycol is attached to the interferon molecule. [Note, PEG-Intron uses different, earlier/1st generation, straight/non-branched PEG chain technology licensed from Enzon, Inc.].

In late 1998, Enzon, Inc. filed a patent infringement suit against Shearwater Polymers (now Nektar) alleging infringement of its U.S. patent 5,643,675 in connection with the manufacture of Pegasys by Roche. This patent (and foreign equivalents) covers Enzon’s second-generation pegylation technologies, “Branched PEG,” involving a unique form of high molecular weight PEG with branched side chains.

In Jan. 2000, Hoffmann-La Roche Inc. filed suit in U.S. District Court alleging that PEG-Intron from Schering-Plough Corp., manufactured using straight-chain PEG technology licensed from Enzon, infringes its U.S. patent 5,792,834 concerning PEG-interferon alpha conjugates. Roche alleged that PEG-Intron is covered by claim 2. This patent and claim involves novel PEG-protein conjugates (e.g., PEG-interferon) using specific linkers to connect free amino groups in the protein to PEG polymers.

In fall 2000, Enzon, Inc. filed suit in federal court against Hoffmann-La Roche Inc. alleging infringement by Pegasys of its U.S. patent 6,113,906. This patent is part of the same family as 5,643,575, which formed the basis for Enzon’s earlier infringement suit against Shearwater. U.S. 6,113,906 similarly includes composition-of-matter claims directed to “branched PEG” technology, involving attachment of a branched PEG polymer at a specific site on a protein.

In summer 2001, Schering-Plough and Hoffmann-La Roche Ltd. entered into a (cross-)licensing agreement that settled all patent disputes involving their respective pegylated interferon products, PEG-Intron and Pegasys. The companies ended all related patent litigation in the U.S. and Europe and withdrew opposition filings. The companies cross-licensed to each other all patents applicable to their peginterferon alfa products. This included Schering-Plough’s (but not ICN/Ribapharm’s) patents applicable to use of (peg)interferon in combination with oral ribavirin. Schering-Plough also granted Roche a sublicense to patents concerning the pegylation technology it had licensed from Enzon Corp., and Enzon agreed to dismiss the patent infringement suit it had filed against Roche asserting violation of its branched chain PEG patents. This settlement allowed each company to market its respective peginterferon products, including use of Pegasys in combination with oral ribavirin. The settlement of these patent disputes affecting PEG-Intron and Pegasys set the stage for a major competitive marketing situation that, in many respects, reflected the companies’ earlier intense competition with non-pegylated interferons (See the Market section below).

In early 2002, Enzon, Inc. and Shearwater/Inhale Therapeutic Systems, Inc. (now Nektar) settled their pegylation patent disputes and formed a broad strategic alliance for licensing and development of pegylation technology. Inhale made a one-time payment to Enzon to cover its legal expenses. Inhale now handles licensing of the companies’ combined pegylation patent portfolio. Enzon receives unspecified royalties on sales of products using its technology.

Schering-Plough and Ribapharm/ICN (now Valeant) hold U.S. patents and pending applications related to use of ribavirin for treatment of hepatitis C and combination use of oral ribavirin and alpha interferon (reportedly providing protection to January 2016). See the Interferon alpha-2b, rDNA (Intron A) entry below for further information about ribavirin and related patents, disputes and generic forms of oral ribavirin. Upon Roche receiving approval for use of Copegus with Pegasys, the original developer of ribavirin, Ribapharm, Inc., then a subsidiary of and >80% owned by ICN Pharmaceuticals (which had exclusively licensed oral ribavirin to Schering-Plough for use in combination with its interferon products for treatment of chronic hepatitis C), now Valeant Pharmaceuticals, filed patent infringement suits in the U.S. and Europe seeking to block Roche’s marketing of its own ribavirin (Copegus) in combination with Pegasys for treatment of chronic hepatitis C. By the end of 2002, suits had been filed in the U.S., Netherlands, Switzerland, and Germany. In Jan. 2003, Ribapharm/ICN (now Valeant) and Roche settled ribavirin-related patent disputes, with Roche receiving a license from Ribapharm/ICN, including Roche paying unspecified royalties.

Hoffmann-La Roche has licensed Intraject needle-free injector technology from Weston Medical (London, U.K.) for administration of Pegasys. This was “the first global license agreement for Intraject, the world’s first single-use, disposable, pre-filled, needle-free injector for subcutaneous delivery of injectable liquid pharmaceuticals.” The device is pencil-sized and contains a small pressurized canister attached to a sealed glass capsule containing the medication. By applying light pressure to the top, the canister forces the immediate release of the medication into the tissue of the skin without the pain caused by a needle.

In March 2006, the Indian subsidiary of Roche received an Indian product patent covering peginterferon-alpha2b. Roche became the first non-Indian company to receive a product (composition-of-matter) patent under India’s new patent regime. The patent will be valid for 20 years from May 15, 1997. Roche had applied for the patent under the World Trade Organisation (WTO) rules for post-1995 inventions. Groups representing patients are challenging the validity of the patent.

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 receipt of 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 UAH 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 Dr. Harris created Shearwater Polymers, now Nektar. UAH claimed that Dr. 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.

Pegasys is covered in the first product/composition-of-matter patent approved in India under the country’s new TRIPS-mandated patent regime. Roche received an Indian patent concerning pegylated forms of interferon. The Sankalp Rehabilitation Trust, an organization providing medical and rehabilitation support to injected drug users, has filed a post-grant opposition filing claim alleging lack of novelty due to prior publication.

In June 2012, it was reported that the expiry of 10-year market exclusivity in most EU member states for Pegasys was expiring that month, but that “patent protection extending beyond exclusivity in all major territories remains a constraining factor for the launch of generic peginterferon alfa-2a”.

Trials: Clinical studies have shown Pegasys to be superior to its unmodified recombinant interferon analog (Roferon A) both for monotherapy treatment of chronic hepatitis C and in combination with oral ribavirin. Pegasys provided significantly higher virologic responses while reducing interferon dosing from three times to once weekly. In intent-to-treat analyses of three pivotal Pegasys monotherapy clinical trials enrolling over 1,400 patients treated with 180 µg of Pegasys once weekly, chronic hepatitis C patients without cirrhosis had overall sustained virological responses (SVR) of 35%, and patients with cirrhosis had SVR of 30%, with both of these response levels significantly higher than for Roferon A.

A pivotal Phase III trial in over 1,100 treatment-naive patients at 81 sites in 18 countries showed that the combination of Pegasys plus oral ribavirin is more effective than Rebetron Combination Therapy – the combination of recombinant nonpegylated interferon alfa-2b (Intron A) from Schering-Plough Corp. plus oral ribavirin. This was the first large-scale trial showing superiority of Pegasys plus ribavirin to Rebetron Combination Therapy, then the standard-of-care for treatment of chronic hepatitis C. Patients were divided into three arms receiving either Pegasys (180 µg) plus ribavirin (1,000 or 1,200 mg) (n = 453); Rebetron Combination Therapy involving recombinant interferon alfa-2b (3 MIU; Intron A) plus ribavirin (1,000 or 1,200 mg) (n = 444); or Pegasys (180 µg) plus placebo (n = 224). Patients received interferon treatment once weekly for 48 weeks, and were monitored for an additional 24 weeks. Among enrolled patients, 65% were infected with genotype 1 hepatitis C virus (considered hard-to-treat) and 14% had cirrhosis (liver scarring). At 24 weeks after the end of treatment, 56% of patients in the Pegasys plus ribavirin group exhibited a SVR, compared to 45% for the Rebetron Combination Therapy group and 30% for the Pegasys monotherapy group. Among patients with genotype 1 virus, 46% in the Pegasys plus ribavirin group had a SVR, compared to 37% in the Rebetron Combination Therapy group. In addition to increased efficacy, the most common side effects associated with interferon therapy (e.g., depression and flu-like symptoms) were less frequent in the Pegasys plus ribavirin group compared to the Rebetron Combination Therapy group, and comparable to the Pegasys monotherapy group.

Another randomized Phase III trial in 1,284 patients at 99 sites worldwide showed the combination of Pegasys plus oral ribavirin to have an unprecedented high level of efficacy for treatment of chronic hepatitis C. Patients were stratified by genotype into four treatment groups—Pegasys (180 µg qw) plus ribavirin (800 mg qd) for 24 weeks; Pegasys (180 µg qw) plus ribavirin (1,000-1,200 mg qd) for 24 weeks; Pegasys (180 µg qw) plus ribavirin (800 mg qd) for 48 weeks; and Pegasys (180 µg qw) plus ribavirin (1,000-1,200 mg qd) for 48 weeks. Pegasys was administered once weekly by pre-filled syringe. A SVR was observed in 51% of Pegasys (180 µg qw) plus ribavirin (800 mg qd) recipients for six months after discontinuation of treatment, the highest ever reported, with this achieved for patients with genotype 1 virus, the most difficult to treat of the six hepatitis C virus strains. About 70% of American patients are infected with genotype 1 virus. Among these patients, optimal results were obtained with 48 weeks of Pegasys plus a now-standard dose (once daily 1,000 or 1,200 mg) of oral ribavirin. Among non-genotype 1 patients, a SVR of 78% was attained after only 24 weeks of treatment and using a low daily dose (800 mg) of ribavirin. Previously, efficacy results of this magnitude had required treatment for twice as long (48 weeks). Such a shorter regimen may spare non-genotype 1 patients from an additional, perhaps unnecessary, six months of treatment. The incidence of adverse events, e.g., flu-like symptoms, fatigue and depression, was lower with Pegasys plus ribavirin than has been reported for conventional interferon plus ribavirin. An intent-to-treat analysis provided the highest overall SVR, 61%, ever reported in a prospective chronic hepatitis C study. A low daily dose of 800 mg of ribavirin was also shown to be effective. The record efficacy attained in this trial was in the arm most closely resembling the actual U.S. hepatitis C patient population, and confirmed results from earlier trials. The superiority of Pegasys plus ribavirin vs. conventional non-pegylated interferon plus ribavirin, in terms of tolerability, was also confirmed. Based on these and other trial results, Roche may make claims that Pegasys (plus Copegus) is more effective than PEG-Intron (plus Rebetol, Schering-Plough’s brand of oral ribavirin).

In April 2004, Roche reported results from a 537-patient Phase III trial showing that Pegasys monotherapy is more effective in treating chronic hepatitis B virus (HBV) infection, particularly variant types, than lamivudine (Epivir-HBV; 3TC) a nucleoside analogy drug from GlaxoSmithKline, the current standard drug treatment for chronic hepatitis B. Combining Pegasys with lamivudine did not increase efficacy. Pegasys monotherapy provided liver histological improvements in 47% of treated patients (vs 29% for lamivudine), and reduced viral load below target levels ( <20,000 copies/mL) in a higher percentage of patients than did lamivudine. Hepatitis B virus DNA decline from baseline was 2.3 log copies/mL for Pegasys, 1.6 for lamivudine, and 2.4 for Pegasys/Lamivudine. In a small subset of 12 patients (none receiving lamivudine), Pegasys resulted in loss of detectable hepatitis B virus surface antigen (HBsAg) and/or seroconversion, indicative of complete disease remission (cure).

Approval of Pegasys for treatment of chronic hepatitis B virus (HBV) infection was based on one of the largest clinical development programs in chronic hepatitis B, which included three global studies in more than 1,500 patients from 19 countries. Pegasys was shown to be twice as effective as conventional alpha interferon (e.g., Roferon-A from Roche or Intron A from Schering-Plough) for the treatment of the most common, HBeAg-positive, form of chronic hepatitis B in a multinational Phase II trial published in the July 2003 Journal of Viral Hepatitis. In addition, two large-scale multinational Phase III trials in patients with both the HBeAg-positive and HBeAg-negative forms of chronic hepatitis B showed that after 48 weeks of therapy, more patients achieved a sustained response with Pegasys than with lamivudine (Epivir-HBV from GlaxoSmithKline); and that the addition of lamivudine to Pegasys did not improve response rates over Pegasys monotherapy. Phase III study results in HBeAg-negative chronic hepatitis B were published in Sept. 2004 in the New England Journal of Medicine. These studies may well support Pegasys becoming the first-line treatment for chronic hepatitis B.

In the June 30, 2005 issue of the New England Journal of Medicine, results were published from a study in 814 patients supporting recommending Pegasys as a first-line treatment for chronic hepatitis B. The study showed that patients with the most common form of chronic hepatitis B are more likely to achieve lasting remission if they are treated with Pegasys, compared with lamivudine, a nucleoside analog, the current standard of care. Patients were treated for 48 weeks with Pegasys180 mg once weekly plus placebo, lamivudine 100 mg once daily, or a combination of Pegasys and lamivudine. Treatment response was assessed following a 24-week treatment-free follow-up period. Pegasys was more effective in achieving lasting remission than lamivudine in patients with a more difficult-to-treat form of the disease. These authors also concluded that Pegasys can be considered as a first-line therapy for chronic hepatitis B. More patients treated with Pegasys achieved the important treatment goal of HBeAg seroconversion, compared with those treated with lamivudine. Patients with hepatitis B in remission after treatment with Pegasys were unlikely to need further treatment, and their risks of developing cirrhosis, liver failure and liver cancer were reduced.

In Dec. 2005, FDA granted approval for Ribasphere, a generic form of Rebetol (ribavirin) from Par Pharmaceutical Co. and Three Rivers Pharmaceuticals LLC (acquired by Kadmon Pharmaceuticals LLC in fall 2010). FDA approved Ribasphere in 200, 400 milligram and 600 mg tablets. Also, in Dec. 2005, Teva Pharmaceutical Industries Ltd. received approval for its generic 200 mg ribavirin tablets.

In Nov. 2007, final results from the REPEAT (REtreatment with PEgasys in pATients Not Responding to Peg-Intron Therapy) study in 950 HCV patients showed that treatment with once-weekly Pegasys plus Copegus for 72 weeks is a promising treatment option for patients whose infection did not respond to previous treatment with another pegylated interferon (PEG-Intron) and ribavirin. Response at 12 weeks was a powerful predictor of the eventual outcome: the majority of patients with undetectable virus at 12 weeks went on to achieve a sustained virological response (SVR) after 72 weeks of treatment, while few patients with detectable virus at 12 weeks achieved SVR.

In Jan 2008, Schering-Plough reported results from its IDEAL (Individualized Dosing Efficacy vs. Flat Dosing to Assess optimaL pegylated interferon therapy) Phase IIIb trial directly comparing PEG-Intron plus ribavirins with Pegasys plus ribavirin (Copegus). The results showed that sustained virologic response (SVR), the primary endpoint of the study, was similar for the two leading combination therapies for hepatitis C. The study also showed that fewer patients treated with both PEG-Intron regimens relapsed after the end of treatment compared to those receiving PEGASYS plus ribavirin. Both PEG-Intron regimens utilized weight-based ribavirin dosing. In the study, 3,070 previously untreated U.S. patients with HCV genotype 1, the most common form of the virus worldwide and the most difficult to treat, were randomized to one of the three treatment regimens and received up to 48 weeks of combination therapy with 24 weeks of follow-up. The three treatment regimens studied were: pegylated interferon alfa-2b 1.5 mcg/kg/week and ribavirin 800-1,400 mg/day; pegylated interferon alfa-2b 1.0 mcg/kg/week and ribavirin 800-1,400 mg/day; and pegylated interferon alfa-2a 180 mcg/week and ribavirin 1,000-1,200 mg/day. SVR, the primary endpoint of the study, was similar for the three treatment regimens (40 vs. 38 vs. 41 per cent, respectively). IDEAL also showed that, while end of treatment response was higher in the PEGASYS RBV arm, fewer patients receiving PEGETRON therapy relapsed after the end of treatment (24 vs. 20 vs. 32 percent, respectively). In many respects, with comparable results, this was as much or more of a positive outcome for Pegasys, the market leader, than for PEG-Intron.

In the Dec. 4, 2008 issue of the New England Journal of Medicine, results were reported from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Phase III trial. Patients with chronic hepatitis C and advanced liver disease receiving long-term pegylated interferon significantly decreased their liver enzymes, viral levels and liver inflammation, but the treatment did not slow or prevent the progression of serious liver disease. HALT-C was funded by the National Institutes of Health (NIH) with additional support from Hoffmann-La Roche Inc. Peginterferon therapy for up to 48 weeks is standard for chronic hepatitis C. But patients who do not have a sustained viral response (SVR) to initial therapy have been given the peginterferon over a longer time based on studies showing that this approach suppresses viral and enzyme levels, even if the virus is not completely eliminated. However, it was not known if long-term therapy would improve important clinical outcomes such as liver damage and death. HALT-C was a randomized multicenter trial of 1,050 patients with chronic hepatitis C who had failed prior treatment to eradicate the infection. The 517 patients randomized to the treatment arm received 90 micrograms of peginterferon in weekly injections for 3.5 years. The 533 patients in the control arm underwent the same follow-up and care as the treated patients. The primary outcomes studied were death, liver cancer, or liver failure, and for those who did not have cirrhosis initially, the development of cirrhosis. At the end of the study, 34.1% of the treated group and 33.8% of the control group had experienced at least one outcome. Patients in the treated group had significantly lower blood levels of the hepatitis C virus and improvement in liver inflammation, but there was no major difference in rates of any of the primary outcomes between the groups. The general conclusion was that Patients should not receive (pegylatated)interferon as maintenance therapy for chronic hepatitis C.

Medical: At the time of the original approval of Pegasys, the standard-of-care for treatment of chronic hepatitis C had recently changed from alpha interferon (Intron A or Roferon A) monotherapy to Rebetron Combination Therapy (Intron A plus oral ribavirin). This then changed to peginterferon monotherapy for a short period until approval of PEG-Intron monotherapy. By early 2003, combination regimens involving use of a pegylated interferon (PEG-Intron or Pegasys) with oral ribavirin (Rebetol or Copegus) had rapidly replaced monotherapy use of pegylated interferon as the standard-of-care for treatment of chronic hepatitis C.

The recommended dosage is one weekly subcutaneous injection of 180 µg of peginterferon alfa-2a for all chronic hepatitis C patients, regardless of body weight (unlike PEG-Intron, with its dosage based on weight). Copegus, 800 to 1,200 mg/day total, taken as 200 mg tablets (or solution) twice daily for treatment of chronic hepatitis C may be added to this regimen.

The recommended dosage for treatment of chronic hepatitis B is Pegasys given once weekly as a 180 µg subcutaneous injection for a 48-week period.

The recommended length of Pegasys treatment for patients is now (2009) based on their virus genotype and type of prior treatment. For patients with genotype 1 virus who did not respond to initial treatment with pegylated interferon and ribavirin, it is recommended (in the EU) that they be retreated with Pegasys for an extended period of 72 weeks. Pegasys is now the first and only pegylated interferon to be approved for a 72-week treatment duration in this patient population. For all other treatment-experienced patients, the recommended treatment period is 48 weeks.The label (EU) recommends that after 12 weeks of treatment, a patient’s virus levels be measured to determine whether a full course of treatment is likely to result in a cure..

Market: Total were about $1.8 billion in 2012; $1.476 billion in 2011; $1.688 billion in 2010. 2009 sales were $1.538 billion; $1.408 billion in 2009; and $1.328 billion in 2007. Total 2006 Pegasys sales reported by Roche were CHF 1.467 billion (~$1.204 billion, at 7/2007 exchange rate), up 3% from 2005 (~$1.17 billion, based on 2006 $ exchange rates). Total sales of Pegasys plus Copegus were reported to be ~$1.26 billion (achieving blockbuster status) in 2004; $762 million in 2003; and total Pegasys sales were $24 million in 2002 (approved late in year).

Total 2005 worldwide sales of Copegus by Roche were reported to be $206 million (at the time of approval, Dec. 2005, of generic Copegus from Teva).

Most analysts correctly projected peak sales of Pegasys (plus Copegus) to be ~$1.1-$1.5 billion or more five years post-approval (2006). However, most analysts expected Schering-Plough Corp. (now Merck) to retain its marketing dominance in the interferon/peginterferon market. Pegasys now is is the largest-selling pegylated interferon, with the market share for Pegasys increasing at the expense of PEG-Intron from Schering-Plough. In fall 2003, Schering-Plough reported that the market share for PEG-Intron rapidly fell from 89% in 2002 to 63% in 2004.

Approval and adoption of Pegasys for treatment of chronic hepatitis B would greatly expand its market. The CDC estimates there are ~1.25 million persons in the U.S. chronically infected with hepatitis B, and 5,000-6,000 deaths annually. The prevalence of hepatitis B virus infection is higher in China and other Far Eastern markets.

The 2007 Average Wholesale Price (AWP) for Pegasys Monthly Convenience Package with one month supply is $1,907.66; $476.93 for one 180 µg/mL 1 mL vial (Red Book, 2007).

The 2007 Average Wholesale Price (AWP) for Copegus is $1,633.57 for 168 tablets (200 mg) (Red Book, 2007), unchanged from 2006. The AWPs in 2005 were $1,226.77 for 168 tablets (200 mg) ($1,071.89 in 2004).

At 2007 AWP rates, the cost for one year of Pegasys treatment is about $22,900 ($18,840 in 2005, ~$17,600 in 2004).

In April 2008, Roche reported that despite gaining market share, U.S. sales of Pegasys have declined as fewer patients sought commercial treatments and waited to enroll in clinical trials for newer therapeutics. Pegasys had sales of $79 million in the U.S. during the first quarter, a decline of 10% compared with the same period in 2007. Pegasys’ market share increased to 65% during the quarter. Throughout 2007, sales of Pegasys (peginterferon alfa-2a), for the treatment of hepatitis B and C remained strong despite an overall decline in market volume in the US and Western Europe. Growth was particularly strong in emerging markets such as China and Turkey.

Pegasys (plus Copegus) primarily competes with PEG-Intron (plus Rebetol) from Schering-Plough Corp. (see related entry), and older non-pegylated recombinant alpha interferon products (primarily Intron A and Roferon A) for treatment of chronic hepatitis C (and for various off-label indications:). Roche asserted that results of Schering-Plough's IDEAL trial which showed comparable reductions in sustained virological response for PEG-Intron and Pegasys in HCV patients was a positive for Roche and Pegasys (or more of a positive than for PEG-Intron).

Pegasys (plus Copegus) is in a very good position to compete against PEG-Intron (plus Rebetol) from Schering-Plough for treatment of chronic hepatitis C. Pegasys has stronger supporting statements on its product labeling, a better reputation based on its better results in clinical trials, has demonstrated efficacy for treatment of patients with cirrhosis, a shorter course of treatment is available for easier-to-treat patients, use for a relatively short period (3 months) of Pegasys plus Copgegus treatment can accurately predict whether the patient will respond to longer therapy (allowing termination, if appropriate), peginterferon dosage is fixed (while PEG-Intron is dosed based on weight), and oral ribavirin dosage is customizable.

In Jan. 2004, the U.K. National Institute for Clinical Excellence (NICE),. which sets purchase and use guidelines for the National Health Service (NHS), recommended use of Pegasys or PEG-Intron in combination with oral ribavirin for treatment of adults with moderate to severe chronic hepatitis C. This replaced recommendations issued in 2000 applying only to nonpegylated versions for treatment of chronic hepatitis C. Switching from non-pegylated to pegylated interferon was estimated to cost an additional $366/month/patient.

In Feb. 2006, NICE adopted recommendations for use of Pegasys for treatment of chronic hepatitis B. Pegasys was recommended as a first-line treatment for this indication for the first time ever, Pegasys is recommended as an option for the initial treatment of adults with chronic hepatitis B (HBeAg-positive or HBeAg-negative), within its licensed indications:. This put Pegasys in the same category as lamivudine and non-pegylated interferon alpha products, Intron A from Schering-Plough and Roche’s own Roferon-A. Hepsera (adefovir dipivoxil) from Giliad has also been recommended by NICE as a second line treatment after other therapeutics are not effective or tolerated.

In Aug. 2006, NICE adopted recommendations for use of Pegasys plus Copegus (ribavirin) for treatment of chronic hepatitis C. Patients with mild chronic hepatitis can be offered treatment with Pegasys plus ribavirin, or with Pegasys alone if ribavirin is not tolerated. The decision regarding whether to start treatment immediately or to wait until the disease has reached a moderate stage is left to the patient (and physician). NICE failed to support using Pegasys/Copegus in those under age 18 and in liver transplant patients. NICE asserts the additional cost of combination therapy will be more than offset by the potential of early drug use to delay disease progression, perhaps even preventing the need for a liver transplant at a later stage. With its new recommendations, NICE estimates an additional 3,500 patients will choose to have treatment, at a cost to the NHS of about £25 million a year. However, it may take some time for this to be implemented at the local/regional level. At the time, the Hepatitis C Trust reported that only 21 of the 305 primary care trusts in England had allocated significant additional resources in 2006 to treat patients with hepatitis C.

In May 2010, the U.K. National Institute for Clinical Excellence (NICE) published draft guidance for the treatment of chronic hepatitis C in which it recommended wider use of Pegasys, reflecting changes in the licensed indications:. Combination of Pegasys and ribavirin was recommended for patients who have failed to responded to or have relapsed following initial treatment and for those also infected with HIV. Shortened courses of the combination treatment, in line with the licensed indications:, were also being endorsed as an option.

In 2012 and beyond, sales of Pegasys are expected to increase, with Pegasys and ribavirin used in triple combination treatment regimens with new hepatitis C drugs - Merck & Co’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir), which is also marketed by Janssen-Cilag as Incivo.

R&D: Hoffmann-La Roche Ltd. has licensed nearly worldwide exclusive rights from Ribapharm, Inc., ICN Pharmaceuticals Inc., now Valeant Pharmaceuticals (which licensed it from Metabasis, Inc.), and is developing levovirin (Virmamidine; ICN 17621; 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamide), an L-isomer of ribavirin containing an L-sugar moiety. Schering-Plough previously had an option to license levovirin, but passed on it. This 2nd-generation form of ribavirin potentially offers improved potency and efficacy compared to oral ribavirin for use in combination with interferon products for treatment of chronic hepatitis C. Some analysts have speculated that Roche’s licensing of patent rights to oral ribavirin from Ribapharm/ICN, rather than challenging the company with infringement suits, was more related to assuring continued development and access to levovirin than its interest in licensing oral ribavirin. Pegasys plus levovirin entered its first Phase II trials in June 2003. In June 2004, Valeant began VISER2, the second of two international Phase III trials comparing Viramidine (taribavirin hydrochloride), a next-generation version of ribavirin, plus Pegasys to ribavirin plus Pegasys in about 1,000 patients. VISER1, a similar Phase III trial in 1,000 HCV patients, began in 2004. In Sept. 2006, initial results from VISER2 were reported. The study did not meet the non-inferiority efficacy endpoint on an intent-to-treat basis, with overall response rates of 40% and 55% for the viramidine and ribavirin arms, respectively. However, consistent with the results seen in VISER1, sustained viral response rates in VISER2 trended higher among patients receiving increased exposure on a mg/kg basis in the viramidine arm without a substantial increase in the anemia rate. Valeant then announced it would start a further trials with Viramidine but at higher doses.