Status - approved; marketed

Organizations involved:

Schering-Plough Corp. – R&D; Former

Merck & Co., Inc. –World mark.; Parent

SP (Brinny) Co. – Manuf.

Enzon, Inc. – Manuf. other; R&D; Tech.

Research Corporation Technologies Inc. – Tech.

Oxis International Inc. – Tech.

Hoffmann-La Roche Inc. – Patent dispute

University of Alabama – Tech.; Patent dispute

Shearwater Polymers, Inc. – Tech.; Former

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

Inhale Therapeutic Systems, Inc. –Parent

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

Description: Peginterferon alfa-2b or PEG-Intron Powder for Injection is a lyophilized (freeze-dried) formulation of a pegylated form of recombinant Escherichia coli (E. coli)-expressed interferon alfa-2b (Intron A) protein currently marketed by Schering-Plough. Pegylation involves the covalent linkage of a single inert straight-chain polyethylene glycol (PEG12000) polymer strand with a molecular weight 12 kDa to the interferon molecule. The PEG strand protects the molecule in vivo from proteolytic breakdown, substantially increases its in vivo half-life, and reduces immunogenicity by wrapping around and physically hindering access to the protein portion of the molecule. PEG-Intron is manufactured by Schering-Plough using non-branched (1st generation) pegylation technology licensed from Enzon, Inc. (see Tech. transfer section), unlike peginterferon-2a (Pegasys) from Roche which uses a larger PEG polymer and branched chain pegylation technology from Shearwater/Nektar.

SYLATRON refers to the combination and bundling of Pegasys with ribavirin for treatment of hepatitis C.

PEG-Intron is composed of relatively small 12 kDa PEG polymer bound to interferon alfa-2b, with about 50% of 12 kDa PEG binding at the His34 site of the interferon alfa-2b molecule. Peginterferon alfa-2b is formed by covalent conjugation of interferon alfa-2b with monomethoxy polyethylene glycol (PEG), forming peginterferon alfa-2b. The molecular weight of interferon alfa-2b is 19.271 kDa, and the average molecular weight of peginterferon alfa-2b is 31.4 kDa. The specific activity of pegylated interferon alfa-2b is approximately 0.7 x 108 (70 million IU/mg) protein.

The 12 kDa straight chain PEG side chain of PEG-Intron is smaller and confers somewhat different properties than the larger 40 kDa branched chain PEG side chain used in peginterferon alfa-2a (Pegasys) from Hoffmann-La Roche Inc. Matrix-assisted laser desorption ionization/mass spectrometry (MALDI-MS), high-performance size exclusion chromatography (HPSEC), circular dichroism (CD) analysis and tryptic digestion peptide analysis of peginterferon alfa-2b have shown that the interferon alfa-2b moiety is ~95% monopegylated (only one strand attached), and that the 1˚, 2˚, and 3˚ structures of the interferon alfa-2b moiety are unaltered.

Clinical studies have shown PEG-Intron to be superior to monotherapy with its unmodified interferon alfa-2b component, Intron A, for treatment of chronic hepatitis C. PEG-Intron provides significantly higher virologic responses while allowing a reduction of dosing from three times to once weekly. PEG-Intron in combination with oral ribavirin, e.g., Copegus from Roche, has shown superiority compared to both Intron A monotherapy and Rebetron Combination Therapy [the combination of Intron A from Schering-Plough plus oral ribavirin (Rebetol); see the Intron A entry) for treatment of chronic hepatitis C.

PEG-Intron Powder is packaged in 2 mL vials containing 74 µg, 118.4 µg, 177.6 µg, or 222 µg of lyophilized peginterferon alfa-2b powder, along with a 5 mL vial of PEG-Intron Diluent (Sterile Water for Injection,USP), two disposable 1 mL (Becton Dickinson Safety-Lok) syringes with needles and needle guards, and alcohol swabs. After reconstitution with 0.7 mL of the supplied Sterile Water for Injection for subcutaneous injection, each dosage size respectively contains peginterferon alfa-2b at strengths of 100 µg/mL, 160 µg/mL, 240 µg/mL, and 300 µg/mL. Excipients in each vial are 1.11 mg dibasic sodium phosphate anhydrous, 1.11 mg monobasic sodium phosphate dihydrate, 59.2 mg sucrose and 0.074 mg polysorbate 80 (Tween 80).

The Redipen pen-like single-use disposable devise for subcutaneous injection of PEG-Intron consists of a dual-chamber glass cartridge with one chamber holding PEG-Intron powder and the other holding Sterile Water for Injection USP for powder reconstitution. The device performs reconstitution, dose preparation, and subcutaneous injection using a 30-guage needle. Patients select the proper dosage based on their weight by adjusting a dial. Redipen is offered for single-use delivery of either 50 µg/0.5 mL, 80 µg/0.5 mL, 120 µg/0.5 mL, or 150 µg/0.5 mL.

The dating period for PEG-Intron is 24 months from the date of manufacture when stored at 25˚C (77˚F). The date of manufacture is the date of final sterile filtration of the formulated drug product. The bulk drug substance may be stored frozen for up to 36 months at –80˚C.

Nomenclature: Interferon alfa-2b, rDNA, PEG- [BIO]; PEG-Intron [TR]; Peginterferon alfa-2b [FDA]; PEG-Intron Powder for Injection [full name on insert/labeling]; PegIntron [TR in Europe]; ViraferonPeg [TR in Europe]; interferon alpha-2b, pegylated, recombinant [SY]; PEG12000-IFN alpha [SY]; PegPak [TR; for PEG-Intron used and packaged in combination with Rebetol (ribavirin)]; Cylatron [TR for melanoma treatment]; Peginterferon; Ribavirin [FDA; for PegPak]; NDC 00085-1323-01; NDC 00085-1268-01; NDC 00085-1316-01; NDC 00085-1291-01; NDC 00085-1297-01; NDC 00085-1204-01; NDC 00085-1370-01; NDC 00085-1279-01 [NDC]

Biological.: Peginterferon alfa-2b has biological activity derived from its interferon alpha-2b moiety (Intron A). Although having different pharmacokinetics and other properties than non-pegylated interferon alpha-2b (Intron A), the biological activity, particularly in vitro antiviral and immunotherapeutic activity, of both are substantially the same. About 50% of PEG-Intron is monopegylated on the His(34) residue of the interferon alpha-2b protein, the positional isomer with the highest antiviral potency for attachment of PEG1200. The specific activity for peginterferon alpha-2b in an antiviral cytopathic protection assay was 28%, relative to Intron A. However, the potency of PEG-Intron, as bioactivity independent of protein concentration, is comparable to Intron A at both the molecular and cellular levels. In vivo, the improved pharmacokinetics, particularly longer half-life of peginterferon alpha-2b more than compensates for its lower in vitro specific activity (similar to Pegasys compared to Roferon A).

Clearance (metabolism and excretion) of peginterferon alfa-2b is significantly lower than that of non-pegylated interferon alfa-2b (Intron A). Peginterferon alfa-2b (1.0 µg/kg) has approximately a seven-fold lower mean apparent clearance and a five-fold greater in vivo mean half-life than interferon alfa-2b. Peginterferon alfa-2b has approximately 10-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b. The longer in vivo residence time of peginterferon alfa-2b enables use of a significantly reduced dosing schedule compared to interferon alfa-2b. Also, cumulative administration of less of the active interferon alfa-2b potentially reduces interferon-associated adverse effects. The mean absorption half-life of peginterferon alfa-2b is 4.6 hours; maximal serum concentrations (Cmax) occur at 15-44 hours post-dose, and are sustained for up to 48-72 hours. After multiple dosing, the bioavailability of peginterferon alfa-2b increases. Week 48 mean trough concentrations (320 pg/mL) are about 3-fold higher than Week 4 trough concentrations (94 pg/mL). The mean peginterferon alfa-2b elimination half-life is about 40 hours in patients with chronic hepatitis C.

Manufacture: PEG-Intron is manufactured and marketed by worldwide by Schering-Plough Corp. (now Merck & Co., Inc.), CBER/FDA est. no. 0994. Pegylation reagent is obtained from Nektar Therapeutics, Inc., formerly Shearwater Polymers, Inc., now a subsidiary of Inhale Therapeutic Systems, Inc. Peginterferon alfa-2b is manufactured by SP (Brinny) Co. (Innishannon, County Cork, Ireland), a subsidiary of Schering-Plough. Final formulated drug product is filled at this facility, and the unlabeled vials are shipped to Schering-Plough facilities in Kenilworth, NJ, for labeling, packaging, and distribution.

PEG-Intron was developed through a collaboration of Enzon, Inc. and Schering-Plough Corp., which holds exclusive worldwide marketing rights for Enzon’s pegylation technology. Enzon Inc. originally performed pegylation, e.g., for product used in early clinical trials, but is no longer involved in manufacture or marketing of PEG-Intron. Based on royalties and sales reports, Enzon receives about 7.5% royalty on sales of PEG-Intron, with these providing a major portion of Enzon’s earnings.

In Dec. 2000, Schering-Plough Corp. announced that it is building new manufacturing facilities in Singapore. This includes $125 million for facilities to provide additional manufacturing capacity for PEG-Intron.

Therapies Health Management (Claremont, CA) administers the PEG-Intron Access Assurance program for Schering-Plough, monitoring patients prescriptions and tracking inventors to ensure uninterrupted supply for existing patients.

In March 2009, Merck & Co. acquired Schering-Plough in a deal valued at over $41 billion.

FDA class: Biologic BLA

CBER class: Biological Response Modifiers

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

Approvals: Date = 20010119; first approval, BLA; Indication = monotherapy treatment of chronic hepatitis C

Date = 20010807; BLA supplement; Indication = use in combination with oral ribavirin (Rebetol) capsules for treatment of chronic hepatitis C

Date = 20031013; BLA supplement; Indication = approval of Redipen prefilled pen-type injector

Date = 20080327; BLA supplement; Indication = approval of weight-based dosing of Rebetol (800-1400 mg daily) based on patient body weight; and recommendation of a shorter, 24-week course of the combination therapy for patients with chronic HCVgenotype 2 or 3 (based on results from the WIN-R trial)

Date = 20080613; BLA 125196 (full, not supplement); Indication = formal full BLA (not supplemental) approval of PegPak or PEG-Intron used and packaged in combination with Rebetol (ribavirin)

Date = 20081212; BLA supplement; Indication = for use in previously untreated pediatric patients 3 years of age and older with chronic hepatitis C

Date = 20090311; BLA supplement; Indication = Peg-Intron plus Rebetol combination (Sylatron) for treating chronic hepatitis C in patients 3 years of age and older with compensated liver disease

Indications: [full text of the "INDICATIONS AND USAGE” section of the product insert/labeling; from www.pegintron.com, 6/2012]:

1.1 Chronic Hepatitis C
PEGASYS, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Efficacy has been demonstrated in subjects with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and in adult subjects with clinically stable HIV disease and CD4 count greater than 100 cells/mm3.
The following points should be considered when initiating therapy with PEGASYS and COPEGUS:
Use of PEGASYS monotherapy is not recommended for treatment of CHC unless a patient has a contraindication to or significant intolerance to ribavirin. Combination therapy provides substantially better response rates than monotherapy [see Clinical Studies].
Safety and efficacy have not been demonstrated for treatment longer than 48 weeks.
The safety and efficacy have not been established in liver or other organ transplant recipients [see Use in Specific Populations (8.7)].
1.2 Chronic Hepatitis B
PEGASYS is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B infection who have compensated liver disease and evidence of viral replication and liver inflammation.

Status: The BLA was submitted on Dec. 23, 1999 and accepted on Feb. 11, 2000 for standard review (approval decision targeted within 12 months). Schering-Plough had requested priority review status (within 6 months), but subsequently reported that it had expected to receive standard review. Approval was granted on Jan. 22, 2001; approval time of ~1.08 years. Post approval requirements included replacement of the original 5 mL vial of diluent packaged with PEG-Intron with a 1 mL vial. PEG-Intron is exempt from CBER lot release requirements.

Schering-Plough filed a BLA supplement on Feb. 6, 2001, for approval of PEG-Intron in combination with oral ribavirin (Rebetol) from ICN Pharmaceuticals (Ribapharm subsidiary), now Valean Pharmaceuticals, for treatment of chronic hepatitis C in adult patients not previously treated with an alpha interferon product and having compensated liver disease. The application received priority review (decision within 6 months). Upon approval, the combination of PEG-Intron and oral ribavirin quickly replacing Rebetron Combination Therapy (Intron A plus oral ribavirin) and PEG-Intron (or Pegasys) monotherapy as the standard-of-care and market share leader for treatment of chronic hepatitis C, although Pegasys in combination with oral ribavirin has now captured most of the market.

As part of the combination approval, Schering-Plough agreed to conduct post-marketing studies, including a 3,000-patient safety and efficacy study using weight-adjusted doses of ribavirin in combination with PEG-Intron; a study to assess the safety and efficacy of alternative dose regimens of PEG-Intron/ribavirin in patients with hepatitis C genotype 1; and a study of whether a six-month PEG-Intron/ribavirin regimen is as safe and effective as the approved 12-month regimen.

In Oct. 2003, Schering-Plough received approval of the PEG-Intron Redipen Single-dose Delivery System, a pen-like device for subcutaneous injection of PEG-Intron. Redipen was officially launched in Feb. 2004.

Schering-Plough has been conducting a comprehensive post-approval study program with the PEG-Intron and Rebetol combination involving more than 10,000 U.S. patients. Studies include defining the optimal dose and duration of PEG-Intron and Rebetol combination therapy in all hepatitis C virus genotypes; evaluating the safety and efficacy of combination therapy in African-American patients, patients on methadone, and HIV and hepatitis C virus co-infected patients; the effect of treatment on liver cirrhosis; and long-term maintenance therapy in non-responders to prior combination therapy.

In Oct. 2005, European Union (EU) granted supplemental approval of PEG-Intron and Rebetol for a 24-week course of therapy in a subgroup of patients with chronic hepatitis C virus (HCV) genotype 1 infection and low viral load (less than 600,000 IU/ml) who have achieved rapid virologic response, defined as undetectable virus (HCV-RNA negative) at week 4 of treatment that is maintained through week 24. This cuts by half the duration of therapy for a subset of hepatitis C patients with genotype 1 and low viral load. PEG-Intron became the first treatment regimen approved in the EU for a 24-week course of therapy in certain genotype 1 patients. In clinical studies supporting the approval, 92% of patients who met the criteria for early response achieved a sustained virologic response (SVR) with 24 weeks of treatment.

In Dec. 2005, PEG-Intron in combination with Rebetol (ribavirin) capsules received approval in Japan for treatment for chronic hepatitis C in adult patients. Japan first approved the combination in October 2004 to treat only patients with the genotype 1 virus (genotype 1a or 1b) and a high viral load. The new approval allows Peg-Intron and Rebetol to be prescribed for patients with genotype 2 and 3 virus and a high viral load and genotype 1, 2 or 3 virus and a low viral load who did not respond to interferon monotherapy.

Schering-Plough filed for a European Union (EU) approval of PEG-Intron for chronic hepatitis C on Nov. 9, 1999, and approval was granted in mid-2000. EU approval of PEG-Intron plus oral ribavirin (Rebetol) for first-line and other treatment of chronic hepatitis C was granted on March 28, 2001. In Oct. 2003, the EU approved use of PEG-Intron in chronic hepatitis C patients without the need for a liver biopsy to confirm diagnosis. Since the viral eradication rate is high (~88%) for patients with hepatitis C genotype virus 2 or 3 taking PEG-Intron and oral ribavirin therapy, treatment is often indicated even if the biopsy turns out to be benign. Liver biopsy is a factor causing many patients to avoid diagnosis and treatment for chronic hepatitis C.

In Oct. 2004, PEG-Intron received approval in Japan for use in combination with Rebetol (ribavirin) for the treatment of chronic hepatitis C. An estimated 1 to 2 million Japanese are chronically infected with hepatitis C.

In fall 2007, Schering-Plough filed a supplemental MAA for approval of PEG-Intron for the adjuvant treatment of patients with Stage III melanoma.

On Nov. 5, 2007, the European Union granted supplemental approval for 48-week standard-dose PEG-Intron (1.5 mcg/kg once weekly) and Rebetol (ribavirin, 800 - 1,400 mg daily) combination therapy for retreating adult patients with chronic hepatitis C whose prior treatment with interferon alpha (pegylated or non-pegylated) and ribavirin combination therapy or interferon alpha monotherapy did not result in a sustained response. PEG-Intron plus Rebetol is the first and only pegylated interferon combination therapy approved in the EU for retreating both hepatitis C relapsers and nonresponders.

On Jan. 31, 2008, FDA accepted a supplemental sBLA for review and has granted Priority Review status for the adjuvant treatment of patients with Stage III melanoma.

In March 2008, FDA issued a complete response letter for a then-pending sBLA for adjuvant treatment of melanoma.

On June 13, 2008, FDA granted a full BLA (not a supplemental BLA, as one might expect) to PegPak or PEG-Intron used and packaged in combination with Rebetol (ribavirin) for treatment of chronic hepatitis C. As discussed in other parts of this monograph, this combination had long been in use. Note, Intron A in 2009 was the only product approved in both the U.S. and EU for advanced melanoma.

On Dec. 12, 2008, Peg-Intron plus Rebetol (ribavirin) received supplemental BLA approval for use in previously untreated patients 3 years of age and older with chronic hepatitis C. This represented the first and only approved peginterferon in combination with ribavirin for treating pediatric hepatitis C. It is estimated that ~130,000 children in the U.S. are infected with the hepatitis C virus (HCV). The most common mode of HCV infection for pediatric patients is maternal-infant transmission.

In March 2009, Schering-Plough withdrew its then pending MAA for EU approval of peginterferon for treatment of stage III resected melanoma. The filing had been submitted in Sept. 2008. The withdrawal was a preemptive move, with the CHMP taking the view that available clinical data did not support approval (positive benefit-risk profile).

On March 11, 2009, PEG-Intron plus Rebetol combination received FDA aprpoval for treating chronic hepatitis C in patients 3 years of age and older with compensated liver disease. PEG-Intron plus Rebetol became the first and only pegylated interferon combination therapy approved in the U.S. that is not restricted to treatment-naive patients. U.S. physicians now have a treatment option that offers a second chance for success to certain patients who failed prior therapy.

In Oct. 2009, FDA, much as the EU did, refused to approve PEG-Intron for adjuvant treatment of melanoma skin cancer patients undergoing surgery. The application was recommended for approval by the FDA Oncology Drugs Advisory Committee on Oct. 5, 2009. However, on October 30, 2009, the FDA issued a complete response letter to the Merck's supplemental BLA. FDA staff agreed that there was "highly significant" increase in the length of time before relapse with PegIntron, just as with Intron-A. "However, there was no effect on overall survival observed, and substantial toxicity occurred with treatment regimen administered in this study."

Tech. transfer: See the interferon alfa-2b, rDNA (Intron A) entry for coverage of recombinant interferon alpha-2b patents, licensing, and disputes.

U.S. patent 5,951,974, "Interferon polymer conjugates, assigned to Enzon, originally set to expire Nov 10, 2013, had its patent term extended by 435 days to Jan. 19, 2015.

Basic patents covering peginterferon alpha-2b as a composition-of-matter include U.S. 5,951,974, “Interferon Polymer Conjugates.” assigned to Enzon Corp. Schering-Plough has received key use patents including 5,908,621, “Polyethylene Glycol Modified Interferon Therapy,” covering use of peginterferon, including peginterferon alpha-2b, for treatment of chronic hepatitis C.

The Sylatron "Instructions for Use" cite U.S. patents "5,951,974 (expiration in 2013); 6,180,096 (formulations, expiring in 2019); and 6,610,830. This last patent, 6,610,830, "Microbial production of mature human leukocyte interferons," assigned to Genentech/Roche, has obviously be licensed by Schering-Plough, now Merck, expires in 2020.

Schering-Plough exclusively licensed straight-chain pegylation technology from Enzon, Inc. in 1990 for use with interferon products, with Enzon retaining manufacturing rights and receiving unspecified royalties on sales of PEG-Intron. In mid-2000, Schering-Plough revised this agreement, with Enzon receiving a higher royalty rate in exchange for transferring exclusive U.S. market manufacturing rights to Schering-Plough. [Note, Schering-Plough has also received a nonexclusive worldwide license with limited sublicensing rights to patents covering Enzon’s Branched PEG, a second generation and different pegylation technology than used with PEG-Intron].

The basic first generation PEG-protein conjugation technology (licensed from Enzon by Schering-Plough and used with PEG-Intron) was exclusively licensed by Enzon from Research Corporation Technologies (RCT; Tuscon, AZ), including U.S. patent 4,179,337. Enzon has also developed proprietary know-how to significantly improve the PEG Process over that described in its original patents covering this technology. Enzon has received over 30 of its own patents which extend its technology. Proprietary know-how enables the Enzon to control the PEG Process in order to produce the targeted results for the particular substance being modified. This includes proprietary linkers for the attachment of PEG to compounds, the selection of the appropriate attachment sites, and the amount and type of PEG used. Enzon, itself, currently manufactures and markets two products using its first-generation technology, each pegylated enzymes – PEG-adenosine deaminase (Adagen) and PEG-asparaginase (Oncaspar). Newer pegylation technologies are available (e.g., see the Pegasys entry), and Enzon does not foresee its first-generation technology (used with PEG-Intron) being used for development of new products.

Enzon received a nonexclusive license from Oxis International Inc. in August 1997 for use of four U.S. patents covering pegylation technologies – 5,006,333; 5,080,891; 5,283,317; and 5,648,478. The patents concern linkage of low molecular weight forms of PEG to proteins and peptides. Oxis received an unspecified up-front payment, plus maintenance and sub-licensing fees, and receives unspecified royalties on products using its technologies.

Shearwater Corp., acquired in 2001 by Inhale Therapeutic Systems, Inc., renamed Nektar Therapeutics, Inc. in Jan. 2003, provides a proprietary PEG reagent to Schering-Plough for its manufacture of PEG-Intron.

After FDA approval, Schering-Plough filed a patent term restoration (extension) application for PEG-Intron (to extend U.S. 5,951,974), with the company requesting 435 days extension.. In the July 16, 2002 Federal Register, FDA ruled that the regulatory review period for PEG-Intron was 1,271 days (3.5 years) – 877 days for the testing phase, and 394 days for the approval/review phase. The relatively short extension period was due to the late granting date of the patent.

In Jan. 2000, Hoffmann-La Roche Inc. filed suit against Schering-Plough Corp. in U.S. District Court alleging that PEG-Intron infringes its U.S. patent 5,792,834. Roche alleged that PEG-Intron was covered by claim 2. This patent and claim involves novel PEG-protein (e.g., PEG-interferon) conjugates using specific linkers to connect free amino groups in the protein to PEG polymers. [Note, PEG-Intron A does not use “Branched PEG” technology used for Roche’s version of pegylated interferon, Pegasys].

In summer 2001, Schering-Plough and Hoffmann-La Roche Ltd. /Inc. entered into a (cross-)licensing agreement that settled all of their patent disputes concerning their respective pegylated interferon products, PEG-Intron and Pegasys. These disputes are further described in the Pegasys entry above. The companies ended all related patent litigation in the U.S. and Europe and withdrew patent opposition filings. The companies cross-licensed all patents and applications applicable to their peginterferon alfa products, including those related to use of (peg)interferon in combination with oral ribavirin. Schering-Plough also granted Roche a sublicense to patents concerning pegylation technology it had licensed from Enzon Corp. (and Enzon agreed to dismiss a patent infringement suit it had filed against Roche asserting violation of its branched chain PEG patents). This settlement allowed each company to market their respective peginterferon products, including 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, reflects the companies’ competition with their earlier non-pegylated interferon products (Intron A and Roferon A)

See the Pegasys entry for information about other ribavirin patent disputes involving Roche and Pegasys, eventually resolved by Ribapharm/ICN granting Roche a license, allowing Pegasys plus oral ribavirin (Copegus) to compete against PEG-Intron plus oral ribavirin (Rebetol). See the Intron A entry for further discussion of ribavirin (e.g., Rebetol) patents, licensing, and disputes.

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

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. Nektar and Dr. Harris jointly made an upfront payment to UAH totaling $15 million; and Nektar will pay UAH $1 million/year for ten years. UAH dismissed all claims related to 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 Dr.Harris founded 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: In PEG-Intron’s pivotal Phase III monotherapy trial for treatment of chronic hepatitis C, a total of 1,219 adult patients in four cohorts received PEG-Intron once weekly at doses of 0.5, 1.0, or 1.5 µg/kg body weight, or Intron A at a dose of 3 million IU three times weekly. Patients received treatment for 48 weeks with 24 weeks follow-up. All patients had chronic hepatitis C virus (HCV) infection with compensated liver disease, were treatment-naive, positive for HCV RNA, and had elevated levels of serum alanine aminotransferase (ALT). The primary efficacy endpoint was sustained loss of detectable HCV RNA at 24 weeks after the end of 48 weeks of treatment. The patients were 63% male, 91% Caucasian, 70% HCV genotype 1 (harder to treat), and 74% had baseline HCV RNA over 2 million copies/mL. At the end of therapy, 33%, 41%, and 49% of the 0.5, 1.0, or 1.5 µg/kg PEG-Intron recipients, respectively, had loss of detectable serum HCV RNA compared to 24% of Intron A recipients. At the end of follow-up, 18% (p = 0.042), 25% (p ≤ 0.001), and 23% (p ≤ 0.001) of the 0.5, 1.0, or 1.5 µg/kg PEG-Intron recipients, respectively, had loss of serum HCV RNA, compared to 12% of Intron A recipients. Adverse events with PEG-Intron were similar to those for Intron A, with most adverse events mild/moderate and manageable with dose adjustment. Discontinuation rates were similar in all treatment groups (6-11%). The investigators concluded, “All 3 PEG-Intron doses were superior to, but as safe as Intron A.”

For treatment of chronic hepatitis C, PEG-Intron plus Schering-Plough’s oral ribavirin, Rebetol, has been shown in several Phase III trials to be significantly more effective (61% vs. 47%) than Rebetron Combination Therapy, then the standard-of-care, involving non-pegylated interferon alfa-2b (Intron A) plus Rebetol, in achieving a sustained virologic response (loss of detectable virus at 6 months after halt of treatment). The PEG-Intron/ribavirin combination regimen was particularly effective (48% vs. 33%) in attaining sustained virologic response in patients infected with genotype 1 hepatitis C virus, which is generally the most retractable to treatment. Sustained virologic response rates were shown to increase, if patients were able to maintain compliance with the regimen, with patients receiving over 80% of their PEG-Intron/ribavirin treatment having a sustained virologic response rate of 72%, compared to 46% among patients who received less than 80% of their treatments.

In Oct. 2004, Schering-Plough reported results from the Comparison of Peginterferon alfa-2a and Peginterferon alfa-2b Pharmacokinetics and Pharmacodynamics (COMPARE) trial comparing the antiviral activity of PEG-Intron and Pegasys in chronic hepatitis C patients. This was a randomized, double blind, parallel group trial in 36 treatment-naive patients with chronic hepatitis C genotype 1 (the most common type of hepatitis C virus worldwide, although not in the U.S., and the most difficult to treat). Patients received PEG-Intron (1.5 µg/kg/wk) or Pegasys (180 µg/wk) monotherapy for four weeks, followed by four weeks with the addition of ribavirin (13/mg/kg/day). PEG-Intron showed significantly greater antiviral activity vs. Pegasys at week one, with greater maximum antiviral activity (p <0.001) and greater cumulative antiviral activity (p =0.017); and at week 4, with greater maximum antiviral activity (p <0.001) and greater cumulative antiviral activity (p <0.001). The slope of the viral load reduction for PEG-Intron was greater over the eight-week study duration (p <0.002). Also, 72% of PEG-Intron patients achieved at least a 2.0 Log10 reduction in viral load vs. 44% for Pegasys (p = 0.09).

Based on COMPARE results, Schering-Plough has been conducting the Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy (IDEAL) study, involving 2,880 patients that for the first time directly compares PEG-Intron in combination with Rebetol (ribavirin) versus Pegasys in combination with Copegus (ribavirin) in U.S. patients with chronic hepatitis C genotype 1. Presuming results are sufficiently positive for PEG-Intron, this could support marketing and even labeling changes of superiority of PEG-Intron (plus ribavirin) vs. Pegasys (plus ribavirin).

In Nov. 2005, results were reported from the U.S. WIN-R study in 4,913 patients who received weight-based (not the then-approved fixed dosage) Rebetol (800-1,400 mg) plus Peg-Intron. Weight-based Rebetol dosing led to higher rates of sustained virologic response (SVR) and lower rates of relapse compared with flat dose Rebetol (800 mg).

In June 2005 and Jan. 2006, results from studies published in the New England Journal of Medicine showed that an even shorter 12-week course of therapy with PEG-Intron and ribavirin combination therapy was as effective as a 24-week course for patients with hepatitis C virus (HCV) genotype 2 or 3 who had an early response to treatment, defined as HCV RNA negative (undetectable viral load) at 4 weeks. This shorter regimen was not only highly effective in these patients, with 85% achieving a sustained virological response (SVR), but it also was associated with fewer side effects and, consequently, less frequent withdrawals from therapy. Also, patients assigned to 12 weeks of treatment were less likely to require a dose reduction. Maintaining the therapeutic dose is important for achieving a SVR. These findings suggest that patients with chronic hepatitis C genotype 2 or 3 infection who have undetectable virus after 4 weeks of treatment with peginterferon alfa-2b and ribavirin achieve high response rates with only 12 weeks of therapy and do not require 24 weeks of treatment, which offers considerable cost savings.

In the Dec. 2007 issue of Hepatology, results were repoted from WIN-R, a multicenter study of over 5,000 patients with hepatitis C virus (HCV) that showed treatment with weight-based Rebetrol (ribavirin; RBV) in combination with PEG-Intron achieved significantly higher rates of sustained virologic response (SVR) and lower relapse rates compared to combination therapy using a flat dose of RBV 800 mg/day. Superior response was found particularly in patients with the most difficult-to-treat form of the disease, genotype 1 HCV. Efficacy was consistent across all weight groups. For patients infected with genotype 2 or 3, a 24 week course of treatment with flat dose RBV + PEG-IFN was as effective as the standard 48-week course, with better tolerability. In the overall study population, flat dosing of ribavirin was as effective as weight-based ribavirin. However, within the flat-dose cohort of patients with genotypes 2 and 3, sustained response rates showed a slight decline in the higher weight patients given flat-dosed ribavirin. These findings help define optimal therapy for hepatitis C patients, with weight-based-dosed combination therapy significantly more effective than the flat-dosed RBV regimen, especially in more difficult-to-treat patient groups, such as patients with genotype 1 and African-American patients. Among African-American participants with genotype 1 infection, twice as many of these patients cleared the virus when treated with the weight-based RBV regimen vs. the flat dose (21% vs. 10%). The study strongly suggests adopting a 1400 mg/dose for patients who weigh more than 105 kg, with this providing an opportunity for very heavy patients to have the same chance of cure as lighter patients without compromising safety.

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 July 11, 2008 isssue of The Lancet, results were reported from the European Organisation for the Research and Treatment of Cancer 18991 (EORTC) 18991 Phase III trial showing that long-term treatment with PEG-Intron in stage III melanoma patients had a significant and sustained impact on relapse-free survival (RFS). This was the largest positive adjuvant trial ever conducted in patients with stage III melanoma. Patients received either peginterferon alfa-2b adjuvant treatment (n=627) or observation only (n=629) within 70 days of regional lymph node dissection (intent-to-treat population). At 3.8 years median follow up, the risk of recurrence or death was reduced by 18% (hazard ratio [HR] 0.82; 95% CI, 0.71-0.96; P=0.01) in the PEG-Intron arm compared with observation. The four-year RFS rate was 46% versus 39% in the observation arm. PEG-Intron is not approved for treatment of melanoma in either the US or EU.

Medical: PEG-Intron is administered once weekly for treatment of chronic hepatitis C (and for other indications: in clinical trials). For monotherapy, PEG-Intron is administered at 1.0 µg/kg/week for one year. For combination use with oral ribavirin (e.g., Rebetol from Schering-Plough), PEG-Intron is administered at 1.5 µg/kg/week for one year.

Administration of conventional alpha interferon, e.g., Intron 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 PEG-Intron lasts much longer in vivo, resulting in more constant and longer-lasting levels of interferon. The improved pharmacokinetics of PEG-Intron generally result in better suppression of viral replication, and the lower dosage generally results in fewer and/or less severe adverse effects.

The amount of time that a pegylated protein such as interferon is able to remain in the body, e.g., its in vivo half-life, correlates with the size of the PEG strand(s) attached to it. This is one of the bases for which Roche claims clinical superiority for Pegasys vs. PEG-Intron.

Market: Worldwide sales of PEG-Intron were $657 million in 2011; $737 million in 2010; $844 million in 2009; $924 million in 2008; and $911 million in 2007. Worldwide sales of PEG-Intron reported by Schering-Plough were $837 million in 2006, $751 million in 2005, and $563 million in 2004. See the Intron A entry above for information about Rebetron sales.

For the full year 2011, royalty revenues from Pegasys received by Enzon were $40.9 million, compared to $44.9 million for the full year 2010.

The 2007 Average Wholesale Price (AWP) is $418.04/50 µg Redipen; $418.04/50µg vial; $372.04/80 µg Redipen; $438.91/80 µg vial; $460.88/120 µg Redipen; $460.88/120 µg vial; $483.94/150 µg Redipen; and $483.94/150 µg vial (Red Book, 2007).

PEG-Intron is very important to Schering-Plough, providing about 15-20% of its total revenue. Sales have been steadily decreasing in recent years due primarily to competition from Pegasys.

Peginterferon alfa-2a (Pegasys) from Roche received FDA approval for chronic hepatitis C after market launch of PEG-Intron for chronic hepatitis C (see Pegasys entry). This provided PEG-Intron considerable time to establish itself as the market leader. PEG-Intron competes directly with Pegasys, including for both monotherapy and combination use with oral ribavirin. The approval of stand alone or unbundled ribavirin (see Intron A entry) allowed ribavirin to be purchased separately for use in combination with either PEG-Intron or Pegasys. Subsequently, Roche has received approval for its own oral ribavirin, Copegus, and multiple generic versions have received approval and entered the U.S. market. With Rebetol approval, Peginterferon/ribavirin combinations quickly became the standard-of-care for treatment of chronic hepatitis C, replacing Rebetron Combination Therapy (Intron A plus oral ribavirin/Rebetol) as the standard-of-care. PEG-Intron plus oral ribavirin/Rebetol and Pegasys plus oral ribavirin/Copegus now compete heavily against each other worldwide (much as Intron A and Roferon A from the same companies previously did).

In Dec. 2002, Schering-Plough reported that the U.S. launch of PEG-Intron plus its oral ribavirin, Rebetol, combination therapy was its most successful ever in terms of product sales, with more than 150,000 hepatitis C patients in the U.S. receiving this therapy since its introduction in Oct. 2001.

The market share for PEG-Intron (plus ribavirin) has been steadily decreasing as Pegasys (plus ribavirin) from Roche increases its market share. In Nov. 2003, Schering-Plough reported that PEG-Intron had fallen to 2nd place in the hepatitis C therapeutics market, with Pegasys holding 52%; and warned that Pegasys’ market share could peak at 60%. Pegasys (plus ribavirin) offers some advantages over PEG-Intron (plus ribavirin), including having shown improved efficacy in large trials. Schering-Plough also made a mistake in cutting its sales force 10% in 2002. The company had been struggling with a dramatic drop in sales for its blockbuster allergy drug, Claritin, now sold over the counter, and other major problems. The company subsequently had to work to restore its sales force.

During May 2004, among the major interferons for hepatitis C (PEG-Intron, Intron-A Redipen, and Pegasys), a total of 1,938 prescriptions were filled for PEG-Intron (24.8% market share), including 648 new prescriptions. For comparison, Pegasys held a 63.0% market share.

Schering-Plough’s wholesale price for PEG-Intron upon its original launch for monotherapy was $962 to $1,114/month ($11,544 to $13,368/year) of treatment. For comparison, Rebetron Combination Therapy (Intron A plus oral ribavirin) was reported to cost $1,560/month and Intron A monotherapy about $480/month. This pricing reflected the relative efficacy of the products as observed in chronic hepatitis C clinical trials, with PEG-Intron plus ribavirin more effective than Rebetron Combination Therapy, Rebetron Combination Therapy more effective than PEG-Intron monotherapy, and PEG-Intron monotherapy clearly superior to Intron A monotherapy.

Schering-Plough priced the combination of PEG-Intron and oral ribavirin at a further premium compared to PEG-Intron monotherapy. The addition of ribavirin (Rebetol) from Schering-Plough, for a time the only oral ribavirin available, added about $1,000 or more per month to the cost of treatment (while ribavirin is readily available at much lower prices in other countries where it has been marketed for years for a variety of non-hepatitis C antiviral indications:). The cost for treatment with PEG-Intron plus Rebetol is reported to be about $24,000/year. Copegus, oral ribavirin from Hoffmann-La Roche, approved for use in combination with its peginterferon (Pegasys), has been priced at about half the cost of Rebetol from Schering-Plough (giving it and Pegasys a marketing advantage). More recently approved, less expensive generic versions of oral ribavirin are now available.

Many hepatitis C patients receive PEG-Intron (and ribavirin) at no cost. For example, in Dec. 2002, 25% of all hepatitis C patients in the U.S. treated with PEG-Intron were enrolled in Schering-Plough’s Commitment to Care program, which provides free therapy and/or reimbursement assistance. The market value of the assistance provided to hepatitis C patients through this program in 2002 was >$100 million.

The Oct. 2003 approval of the RediPen prefilled injector device was significant, allowing PEG-Intron to better compete with Pegasys in terms of patient convenience.

In Oct. 2006, results from the ongoing EPIC3 study were reported, showing that retreatment with PEG-Intron and Rebetol combination can result in sustained virologic response (SVR) in patients with chronic hepatitis C having failed previous treatment with any alpha interferon-based combination therapy, including peginterferon regimens. In this study, 56% of patients who had undetectable HCV RNA after 12 weeks went on to achieve SVR with a 48-week course of therapy. Of the first 1,354 patients retreated, ~38% had undetectable virus at week 12. Importantly, patients who did not have undetectable virus at 12 weeks had little chance of achieving SVR. The results suggest undetectable viral load at week 12 defines an early virologic response that predicts SVR for patients who failed previous combination therapies and are retreated. Besides showing efficacy of retreatment with PEG-Intron/ribavirin, a large and growing pool of p7 atients, efficacy of (re)Treatment with P egasys plus Copegus (ribavirin) has been considered more predictable, based on early viral load reductions, and these new results may help PEG-Intron in its direct competition against Pegasys.

Competition:      Viragen (Scotland) Ltd., a subsidiary of Viragen (Europe) Ltd., has formed a collaboration with PolyMASC Pharmaceuticals plc, a subsidiary of Valentis, Inc., for development of a pegylated form of Viragen’s natural leukocyte-derived alpha interferon, Omniferon (currently in clinical trials). PolyMASC uses pegylation technology developed by the Molecular Cell Pathology Lab., Royal Free Hospital School of Medicine (London, U.K.). Positive results from a Phase IB trial in combination for treatment of chronic hepatitis C in combination with an antiviral drug from Wyeth were reported in Aug. 2006.

ZymoGenetics, Inc. is developing PEG-Interferon lambda for hepatitis C and other viral diseases. Phase I trials began in Jan. 2007. In Jan. 2009, Bristol-Myers Squibb Co. and ZymoGenetics, Inc. formed a collaboration for development of PEG-Interferon lambda, a type 3 interferon then in Phase Ib development for the treatment of hepatitis C.

Cyplasin Biomedical is developing a biosimilar version of PEG-Intron. Minapharm Pharmaceuticals will distribute and market this version of the long-acting pegylated interferon-alpha product (to be marketed and sold under Cyplasin's brand name C-Pegferon within the North American and South American markets as well as Mexico, Latin America, Korea, Russia, China, India and other countries.