Interferon gamma-1b - Actimmune
Status - approved; marketed
Organizations involved:
Genentech, Inc. – Manuf.; R&D; Tech.; Former
Hoffmann-La Roche Ltd. – Parent
InterMune Pharmaceuticals Inc. – U.S. mark.
Connetics Corp. – Parent; Former
Boehringer Ingelheim Pharma KG – Manuf.; Intl. mark.
Biogen Corp. – Tech.; Former
Biogen Idec – Tech.
Amgen Inc. – Patent dispute; Tech.
Daiichi Pharmaceuticals Co. – Tech.
Toray K.K. – Tech.
Columbia University – Tech.; Patent dispute
City of Hope National Medical Center – Tech.; Patent dispute
Cross ref.: See the Interferon Products entry in the Blood Products, Human section.
Description: Interferon gamma-1b or Actimmune is a formulation of recombinant single-chain non-glycosylated N-methionyl interferon gamma-1b polypeptide expressed in Escherichia coli (E. coli) strain K-12 transformed with the gene encoding native human interferon gamma-1b, with the N-terminal methionine residue resulting from expression in E. coli. Interferon gamma-1b, like native human interferon gamma molecules, exists in aqueous solution as non-covalently linked dimers composed of two linked identical 16,465 Dalton (16.47 kDa; molecular formula of C734H1166N204O216S5) monomeric interferon gamma polypeptides.
Interferon gamma (recombinant and native human forms) exhibits antiviral and anti-proliferative properties characteristic similar to other interferon species. However, in contrast to leukocyte (alpha) and fibroblast (beta) interferons, interferon gamma (immune interferon) is labile at pH 2 (acid-labile or unstable at acid pH). Potency of Actimmune is expressed as units/vial in an antiviral assay using the World Health Organization (WHO) natural human interferon-gamma standard as a reference standard. The value of 3 x 107 (30 million) units/mL for Genentech’s reference standard for recombinant interferon gamma-1b is used to assign the potency of production lots of Actimmune using an HLA-DR bioassay. Activity was formerly reported as units, with Actimmune having a specific activity of 30 million U/mg. Activity is currently reported in International Units, with Actimmune having a specific activity of 1 million IU/50 µg.
Actimmune is packaged in single-dose vials for subcutaneous injection. Each 0.5 mL vial of Actimmune contains: 100 µg (2 million IU) of interferon gamma-1b formulated in 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate 20 (Tween 20) and Sterile Water for Injection.
Nomenclature: Interferon gamma, rDNA [BIO]; Actimmune [TR orig. reg. to Genentech, now InterMune]; interferon gamma-1b [FDA]; Interferon Gamma-1b [USAN BAN INN]; N2-L-methionyl-1-139-Interferon gamma (human lymphocyte protein moiety reduced) [CAS]; 98059-61-1 [CAS RN]; 82115-62-6 [CAS for human interferon gamma]; Immukine [TR in U.K.]; Imuforgamma [TR in Germany]; Imukin [TR in Spain, France, Denmark, Sweden, Austria]; antigen-induced interferon [SY]; type-2 interferon [SY]; mitogen-induced interferon [SY]; pH2-labile interferon [SY]; acid-labile interferon [SY]; immune interferon [SY]
Biological.: Human gamma interferon is antigenically and structurally distinct from the leukocyte, e.g., alpha, and fibroblast, e.g., beta, interferons. Prior to the manufacture of gamma interferon by recombinant methods, interferon gamma had been produced mainly by mitogenic induction of cultured peripheral lymphocytes. Gray, Goeddel, et al. (Genentech) were the first to report recombinant expression of what was claimed to be human interferon gamma (Nature, 295, 503-508, 1982). This recombinant interferon gamma produced in E. coli consisted of 146 amino acids, with the N-terminal portion of the molecule starting with the sequence Cys-Tyr-Cys. However, native human gamma interferon (i.e., that arising from mitogen induction of human peripheral blood lymphocytes and subsequent purification) was subsequently shown to be a polypeptide lacking the CYS-TYR-CYS-N-terminus assigned by Gray et al. The recombinant interferon gamma-1b in Actimmune differs from this originally described/patented molecule, having the amino acid sequence of native human interferon gamma but with an N-terminal methionine residue (an artifact encoded by the mRNA translational “start” signal AUG for E. coli expression, which is not removed by this bacterial host system).
Interferon gamma has been characterized as an interleukin-type lymphokine, because it is produced by antigen-stimulated T-lymphocytes (T-cells), and because of its regulatory effects on immune cell activity. Interferon gamma appears to interact with other interleukins such as interleukin-2 (IL-2) involved in regulation of the immune system. Unlike interferon alpha and beta, interferon gamma has potent phagocyte-activating properties. The mechanism of action of interferon gamma involves enhancement of oxidative metabolism in macrophages; and enhancement of antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell activity, both involved in cellular immunity. Enhancement of macrophage oxidative metabolism results in the production of toxic oxygen metabolites (e.g., oxygen and free radicals) within phagocytes, which facilitates more efficient elimination of certain fungi, bacteria, and protozoa.
Companies.: Interferon gamma-1b and Actimmune were originally discovered and developed, and Actimmune was originally manufactured and marketed in the U.S. by Genentech, Inc. (now part of Hoffmann-La Roche), CBER/FDA est. 1048. Genentech also conducted Phase III clinical trials with Actimmune for treatment of infections in patients having endured severe trauma, for renal carcinoma, and as an adjuvant therapy in the treatment of patients with malignant melanoma and small-cell cancer of the lung. Development of Actimmune was at least partially funded through Genentech Limited Partners, L.P. Two Japanese companies, Daiichi Pharmaceuticals Co., Ltd. and Toray K.K., helped finance development of Actimmune (and presumably receive royalties).
InterMune currently markets and distributes Actimmune in the U.S. and Canada.
InterMune Pharmaceuticals, CBER/FDA est. no. 1267, received a BLA for manufacture of Actimmune on Feb. 25, 1999. CBER/FDA considers InterMune as the manufacturer of Actimmune. However, as described in Genentech’s and InterMune’s SEC filings and other sources, Actimmune has been always been manufactured by Genentech, and InterMune has no manufacturing capabilities. Genentech sells the packaged product to InterMune at cost plus a mark-up.
Genentech originally licensed exclusive European manufacturing and marketing rights to Boehringer Ingelheim GmbH, which manufactures and markets its interferon gamma-1b as Imukin (with a different formulation/presentations than Actimmune). Boehringer Ingelheim Pharma KG received FDA approval as a manufacturer of Actimmune in fall 2001, and is now the sole manufacturer of Actimmune for InterMune.
In Dec. 1995, Connetics Corp., a company earlier spun-off from Genentech, exclusively licensed Actimmune U.S. marketing rights from Genentech for dermatological indications: for its InterMune Pharmaceuticals Inc. subsidiary. In May 1998, InterMune/Connetics Corp. further licensed U.S. marketing rights from Genentech for the treatment of chronic granulomatous disease, and U.S. development and marketing rights for all other indications:. Connetics issued stock to Genentech valued at $2 million (with a guaranteed value of $4 million in Dec. 1998), pays development and commercialization milestone fees, and pays Genentech royalties on sales.
InterMune, Inc. was spun-off from Connetics as a separate company in April 1999 and continues to pay royalties to Genentech, from which it purchases Actimmune.
In June 2000, InterMune paid Connetics $5.2 million for Actimmune’s marketing rights that InterMune did not already own, including exclusive Canadian rights, and rights for additional indications:, including osteopetrosis, fungal, bacterial, and viral infections, oncology, pulmonary fibrosis, and asthma. In August 2000, InterMune modified its licensing agreement with Genentech to obtain Japanese rights for Actimmune for all infectious disease indications:. InterMune previously only had rights in Japan for tuberculosis indications:.
On March 26, 2001, InterMune and Boehringer Ingelheim GmbH (BI) formed an international strategic partnership to develop and commercialize interferon gamma-1b (Imukin) in all countries outside of the U.S, Canada and Japan. InterMune assumed clinical and regulatory development. BI retained the option to exclusively promote Imukin in its territories. InterMune has the option to promote the product where BI does not do so. indications: covered include idiopathic pulmonary fibrosis (IPF), tuberculosis, systemic fungal infections, chronic granulomatous disease (CGD) and osteopetrosis.
In Sept. 2001, InterMune received FDA approval (sBLA) for manufacture of Actimmune (for U.S. sales) by Boehringer Ingelheim Austria GmbH (BI; Vienna, Austria), a subsidiary of Boehringer Ingelheim Pharma KG, CBER/FDA lic. no. 1251. BI already manufactured clinical trial supplies of Actimmune for InterMune, and interferon gamma-1b for its own, primarily European, marketing under the trade name Imukin. This facility has capacity to support $500 million annual sales of Actimmune.
Manufacture: Production of interferon gamma-1 is performed by fermentation of a genetically engineered Escherichia coli (E. coli) bacterium strain K12 containing the DNA encoding for the human protein. Purification of the product is achieved by selective precipitation and several conventional column chromatography steps. The final product is prepared in the formulation excipients (mannitol, sodium succinate, polysorbate 20 and Sterile Water for Injection) by concentration using ultrafiltration and conditioning by gel permeation chromatography.
FDA class: Biologic PLA BLA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19901220; first approval, PLA/ELA, granted to Genentech; orphan designation (granted 9/3/1988; expired 12/1997); Indication = for reducing the frequency and severity of serious infections associated with chronic granulomatous disease
Date = 19990225, PLA/ELA revoked and new license, a BLA, granted (reissued) to new owner, InterMune Pharmaceuticals, Inc., subsidiary of Connetics Corp. [product still manufactured by Genentech]
Date = 20000210; BLA supplement; orphan designation; Indication = for delaying the time to disease progression in patients with severe, malignant osteopetrosis
Date = 20010919; BLA supplement; revocation of approval for manufacture by Genentech and approval of manufacture by Boehringer Ingelheim Austria GmbH [However, the October 2002 release of the CBER/FDA Establishments and Products publication/Web site records still reported InterMune as manufacturer with facilities located within Genentech, Boehringer Ingelheim, and Amgen (for manufacture of Infergen)].
Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling]:
ACTIMMUNE is indicated for reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease.
ACTIMMUNE is indicated for delaying time to disease progression in patients with severe, malignant osteopetrosis.
Status: Approval was granted to Genentech on Dec. 20, 1990. Actimmune is exempt from CBER lot release requirements.
InterMune filed a BLA supplement and on Jan. 7, 2002 received fast track designation for use of Actimmune for treatment of idiopathic pulmonary fibrosis (IPF). A substantial number of patients, perhaps half, receiving Actimmune had been using it off-label for this indication. A new pivotal trial for this indication was ongoing (see Trials section) at the time of filing. However, in March 2007, the trial was abruptly halted (see the Trials section), along with development of Actimmune for IPF.
In Nov. 2004, InterMune received a subpoena from a Department of Justice criminal investigation seeking information concerning its marketing of Actimmune, particularly marketing for off-label (unapproved uses). Although approved only for rare pediatric indications:, nearly all of Actimmune’s sales were then for sales are for adult idiopathic pulmonary fibrosis (IPF), which apparently had raised attention.
In Oct. 2006, InterMune entered into a deferred prosecution agreement (out-of-court settlement) and agreed to pay $36.9 million plus 5% interest over five years to resolve charges connected with its promotion and marketing of Actimmune. The payment was for estimated losses suffered by the federal portion of the Medicaid program, the Medicare Program, the Veteran’s Administration, the Department of Defense and the Federal Employees Health Benefits program. Prosecution of InterMune was deferred for two years, contingent upon the company’s cooperation in the investigation and continued efforts to implement comprehensive changes to its compliance policies. Under separate civil settlement agreements, the company will also pay $6.69 million to various state Medicaid programs.
In many respects, Actimmune has been a model for off-label use controversies, e.g., for IPF. Many physicians and patients rushed to use it after initial promising trials results were reported (based on a very small number of patients). Use of the drug has divided the medical community, with some physicians considering it was the best option and others saying more proof was needed, a waste of money, etc.
In March 2007, InterMune suspended its pivotal Phase III trial of Actimmune for treatment of IPF, and the company halted Actimmune development for IPF. See the Trials section below. The company laid-off about half of its staff. InterMune is now concentrating on development of pirfenidone for IPF and chronic hepatitis C infection.
In April 2011, Dr. W. Scott Harkonen, Iormer chief executive officer, Intermune Inc.., was sentenced to six months of home confinement, with 3 years’ probation, and fined $20,000 for his role in disseminating misleading information about Actimmune. Harkonen was convicted by a federal jury of wire fraud in September 2009 after a three-week trial. Dr. Harkonen was found guilty of crafting a deceptive press release in 2002 to boost sales of Actimmune. U.S. District Judge Marilyn Patel also sentenced Harkonen to three years’ probation at a hearing yesterday. The press release cited reduced deaths by 70% in patients with mild to moderate IPF. Intermune had agreed in 2006 to pay $36.9 million to settle improper off-label marketing allegations.
Tech. transfer: U.S. patent 4,727,138, “Human immune interferon,” Goeddel, D.V. and Gray, P., Feb. 23, 1988, assigned to Genentech, Inc., discloses substantially pure recombinant interferon gamma polypeptides produced utilizing an assortment of expression vectors and host cultures. The polypeptides are isolated and characterized in terms of DNA and amino acid sequences, physical attributes, and biological activity.
In Jan. 1990, Biogen Corp. (now Biogen Idec) and Genentech, Inc. entered into a patent cross-license agreement for recombinant interferon gamma in the U.S., enabling each company to develop and market its own product. Biogen also granted Genentech a nonexclusive worldwide license for process patents relating to the secretion of proteins including interferon gamma. Biogen Corp. pursued development of its own interferon gamma (Immuneron), including conducting trials in the U.S. for treatment of rheumatoid arthritis and genital warts due to human papillomavirus (HPV) infection. However, Immuneron did not show efficacy for these indications:. and Biogen discontinued its development.
Interferon gamma patents assigned to Biogen include U.S. 5,004,689, “DNA Sequences, Recombinant DNA Molecules and Processes for Producing Human Gamma Interferon-Like Polypeptides in High Yield,” Fiers, W.C. and Allet, B., April 2, 1990. Biogen also holds U.S. 4,530,901, “Recombinant DNA Molecules and Their Use in Producing Human Interferon-Like Polypeptides, by Weissmann, C., July 23, 1985, broadly covering recombinant expression of diverse mature interferon species (See Intron A entry for further information).
In May 2002, InterMune licensed the interferon gamma-1b patent portfolio of Amgen Inc. This ended “issues” between Genentech and Amgen concerning their respective interferon gamma-related patents in North America and Europe (i.e., legal disputes were avoided).
In Sept. 2004, InterMune reported receiving, “two composition of matter patents that together cover the manufacture, use and sale of Actimmune (interferon gamma-1b)...These patents, USPN 6,936,694 and USPN 6,936,695, expire in 2022 and extend a portfolio of intellectual property rights relating to Actimmune” However, this statement appears to be too simplistic in its claims of covering Actimmune. Both patents are entitled “Manufacture and expression of large structural genes” and concern gamma interferons with amino acid substitutions, not interferon gamma-1b.
Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was seeking further royalties, which Genentech and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech appealed a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent licensing dispute involving COH developing basic cloning technology for Genentech.
Trials: Initial approval was based on a pivotal Phase III 15-patient trial showing that Actimmune significantly delayed the time to chronic granulomatous disease progression compared to a control vitamin D medication (calcitriol) by at least 165 days versus 65 days. In patients treated with Actimmune, there was a statistically significant increase in the time to disease progression (263 days for Actimmune compared to 130 days in the control group; p < 0.016). Disease progression was defined as death, a significant reduction in hemoglobin or platelet counts, a serious bacterial infection requiring antibiotics, a 50-decibel decrease in hearing, or progressive optic atrophy. Actimmune increased five-year survival to 70% compared to 30% for control patients.
Actimmune is commonly used off-label (unapproved) for treatment of idiopathic pulmonary fibrosis (IPF). InterMune began a U.S. randomized, double-blind, placebo-controlled Phase III trial (GIPF-001) with Actimmune in late 2000. A nonsignificant trend toward survival advantage was observed at 12-14 months. The trial was extended another 3-5 months to see if survival advantage improved with longer treatment. However, results announced in Jan. 2003 indicated that the difference between Actimmune and control patients decreased adversely. GIPF-001 results were published in the Jan. 7, 2004 New England Journal of Medicine. In 330 IPF patients, Actimmune failed to show significant prolongation of progression-free survival, the primary endpoint, and 10% of Actimmune patients died vs. 17% of placebo patients (p=0.08). However, a 70% decrease in mortality was noted in a subset of mild to moderately ill patients. The company expected these results not to affect off-label sales for IPF, but the company’s BLA supplement for IPF was significantly delayed, with the filing having to minimally wait for completion of a new trial.
In Oct. 2004, Intermune reported continued progress with its then ongoing Phase III INSPIRE trial with Actimmune monotheray for treatment of idiopathic pulmonary fibrosis (IPF), and Intermune decided to enroll an additional 200 patients without affecting the duration of the study. An interim evaluation at this early point in the trial found the overall mortality rate to be somewhat lower than the projections used in designing the trial. InterMune increased the trial size by an additional 200 patients to take advantage of strong enrollment trends and to increase the likelihood of observing the planned number of total events prior to its completion date. INSPIRE was an 600 patient, randomized, double-blind, placebo-controlled, pivotal Phase III trial in patients with mild-to-moderate IPF. The primary endpoint was decrease in mortality in IPF patients. INSPIRE began in Dec. 2003, and was the largest and most comprehensive IPF trial to date. INSPIRE sought to confirm observations that interferon gamma prolongs survival in patients with IPF (the primary endpoint). Early findings from the prior GIPF-001 trial formed the basis for the design of INSPIRE. In Nov. 2005, the 600th patient, the target number, was enrolled in INSPIRE, with the study expected to conclude in about two years, with top line data to be disclosed in early 2008.
In Jan. 2005, new results from the GIPF-001 trial for IPF treatment were reported. Retrospective analysis of the composite primary efficacy endpoint [death or disease progression as defined by an increase in resting alveolar-arterial oxygen pressure gradient (A-a gradient) of greater than or equal to 5 mm Hg or a decrease in forced vital capacity (FVC) of greater than or equal to 10%] showed that neither of these outcomes was the “preferred outcome measure in future studies of Actimmune in patients with IPF.” Rather, survival was shown to be a robust and sensitive endpoint, with nearly all patient subgroups defined by physiology showing a tendency toward prolonged survival with Actimmune therapy, particularly in patients with baseline FVC of greater than or equal to 55% (p=0.004) or diffusing capacity of greater than or equal to 30% (p=0.008). This supported the design of the INSPIRE trial.
Actimmune has been tested unsuccessfully in Phase III trials for ovarian cancer. A Phase III trial, GRACES (Gamma Interferon and Chemotherapy Efficacy Study), evaluated Actimmune in combination with standard chemotherapy for advanced ovarian cancer. In Feb. 2006, InterMune halted this trial after noting that ovarian cancer patients receiving the Actimmune plus chemotherapy had shorter overall survival than patients on chemotherapy alone. An imbalance in survival time across treatment groups was driven by ovarian cancer-related deaths that occurred during follow-up after completion of the study treatment period. Intermuune has no plans for any further oncology studies of the product.
Actimmune has been tested unsuccessfully for other indications:. Development for treatment of renal cell carcinoma was dropped after Phase III studies revealed no significant benefit. Actimmune was also tested in a Phase III trial for treatment of atopic dermatitis, but failed to show significant efficacy, and development for this indication was dropped. Biogen had conducted trials with interferon gamma without success for rheumatoid arthritis and genital warts (herpes simplex virus type 2 infection). InterMune conducted a 500-patient, double-blind, placebo-controlled Phase II study for the treatment of liver cirrhosis due to chronic hepatitis C (HCV). In Jan. 2004, InterMune reported that Actimmune failed to reverse liver fibrosis, the trial’s primary endpoint, and the company halted development for this indication.
In March 2007, the pivotal Actimmune monotherapy Phase III INSPIRE trial for IPF was abruptly halted by the study’s independent data monitoring committee. In an analysis that included a total of 115 deaths, the overall survival result crossed a predefined stopping boundary for lack of benefit of Actimmune relative to placebo. Among the 826 randomized patients, there was not a statistically significant difference between treatment groups in overall mortality (14.5% in the Actimmune group as compared to 12.7% in the placebo group). Adverse events associated with Actimmune appeared generally consistent with prior clinical experience, including constitutional symptoms, neutropenia and possibly pneumonia. IPF remains a disease with no approved therapeutics.
In mid-2007, Actimmune continues in the already ongoing Phase III CAPACITY for IPF in combination with pirfenidone; this was the only advanced trial ongoing with Actimmune; and development of Actimmune monotherapy for IPF has been abandoned.
Medical: Actimmune is used for treatment of chronic granulomatous disease (CGD), a rare, inherited deficiency (genetic disease) of the immune system (phagocytic oxidative metabolism) that leaves patients vulnerable to frequent and severe bacterial and fungal infections. These infections often require hospitalization and can be fatal. Actimmune produces approximately a threefold reduction in the frequency and severity of serious infections associated with CGD. Results from clinical trials with Actimmune for CGD were published in the New England Journal of Medicine, Feb. 1991. Prior to the availability of Actimmune, the standard treatment for CGD included surgical drainage of abscesses, extended systemic antimicrobial prophylaxis, and leukocyte transfusions.
The recommended dose is one 2 million IU subcutaneous injection weekly.
The most frequent side effects associated with Actimmune include those associated with other interferons – flu-like symptoms such as fever, headache, muscle soreness, malaise and chills. Side effects may be minimized by bedtime administration and may decrease in severity as treatment continues.
Actimmune is also approved for treatment of osteopetrosis (not osteoporosis), a potentially fatal congenital disorder (genetic disease) in which bony overgrowths can cause loss of sight and hearing, as well as organ damage. Actimmune was the first treatment approved specifically for osteopetrosis. There previously had been no known treatment for this disorder other than bone marrow transplantation, which is successful in only a minority of cases.
Market: Total sales of Actimmune by Intermune were $53.7 million in 2007, ~$90 million in 2006, $107.3 million in 2005, $125.0 million in 2004, $141.4 million in 2003, $105.8 million in 2002; $36.2 million in 2001; $14 million in 2000, $4.8 million in 1999, $3.9 million in 1998, and $3.5 million in 1997.
The disappointing results reported from the INSPIRE idiopathic pulmonary fibrosis (IPF) trial in March 2007 will likely result in significant loss of sales for Actimmune. A majority of Actimmune use has been off-label for IPF.
The 2007 Average Wholesale Price (AWP) is $254.02/0.5 mL, 2 million IU/0.5 mL vial, and $3,148.89 for 12 (Red Book, 2007). The 2004 AWP was $254.02/0.5 mL, 2 million IU/0.5 mL vial ($247.34 in 2004), and $2,771.05 for 12 vials ($2,968.20 in 2004).
Treatment with Actimmune is generally reported to cost about $50,000/year.
Both of Actimmune’s currently approved indications: are for rare genetic diseases, with Actimmune easily qualifying for orphan drug designation for each of these. There are only an estimated 400 patients in the U.S. with chronic granulomatous disease (CGD). Osteopetrosis affects only 50-100 newborns in the USA each year.
With its approvals restricting much of its use to relatively few pediatric patients, sales of Actimmune have been primarily driven by off-label (unapproved) use, particularly for adult idiopathic pulmonary fibrosis (IPF). However, Actimmune monotherapy for IPF (INSPIRE trial) was shown in March 2007 to not provide a survival benefit and its further development has been abandoned, while Actimmune continues in a Phase III combination trial (see the Trials section above). This disease affects about 80,000 persons in the U.S., and there are currently no effective or approved treatments. Results from an independent clinical study reported in late 1999 indicated Actimmune monotherapy has efficacy for IPF, and sales for this indication steadily increased since then. Although InterMune’s completed GIPF-001 Phase III trial for IPF did not attain its primary endpoint (progression-free survival), a 70% decrease in mortality was noted in a subset of mild to moderately ill patients, which encouraged off-label use in IPF patients. This group was further tested in the INSPIRE trial. Actimmune could potentially become a blockbuster (over $1 billion annual sales), if approved and adopted for treatment of IPF. Even if it is not approved for IPF and despite its lack of survival improvement as monotherpy, off-label sales for IPF may continue.
As mentioned in the Status section above, InterMune received a subpoena in Nov. 2004 from the Department of Justice regarding an investigation of its off-label Actimmune marketing practices. This was settled in Oct. 2006 with the company paying over $36 million to settle the case.
R&D: InterMune is working with Maxygen, Inc. on a next generation interferon gamma for once weekly dosing. In Aug. 2005, Bolder BioTechnology, Inc. received a $121,844 Phase I Small Business Innovation Research (SBIR) grant from the National Cancer Institute (NCI), National Institutes of Health (NIH), for development of a long acting gamma interferon analog for the treatment of ovarian cancer.
Various companies are developing biogeneric, biosimilar, follow-on biologics, etc. versions of interferon gamma. For example, Therapeutic Proteins, Ltd. (U.K.) is developing a biosimilar/biogeneric interferon gamma product. Multiple versions of interferon gamma are already marketed in China and other lesser-developed countries (wherever lack of patents or their enforcement allows).
Companies involvement:
Full monograph
213 Interferon gamma, rDNA
Nomenclature:
Interferon gamma, rDNA [BIO]
Actimmune [TR formerly Genentech, now assgined to InterMune]
Interferon gamma-1b [FDA]
Interferon Gamma-1b [USAN BAN INN]
1-139-Interferon gamma (human lymphocyte protein moiety reduced), N(sup2)-L-methionyl- [CAS; gamma is Greek letter]
82115-62-6 [CAS RN for human interferon gamma]
98059-61-1 [CAS RN]
immune interferon [SY]
Imukin [TR in Europe; reg. to Boehringer Ingelheim]
antigen-induced interferon [SY]
Immukine [TR in U.K.]
Imuforgamma [TR in Germany]
mitogen-induced interferon [SY]
pH2-labile interferon [SY]
type-2 interferon [SY]
C734H1166N204O216S5 [MF USAN]
molecular weight (kDa) = 16.5
FDA Class: Biologic PLA BLA
Year of approval (FDA) = 1990
Date of 1st FDA approval = 19901220
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2022, based on 6,936,694 and 6,936,695, as claimed by Intermune (and also RE39821, a reissue of 6,936,694), but see monograph text regarding doubts about relevancy to Actimmune |
U.S. Patent Expiration Year: | 2022 |
U.S. Biosimilars Data Exclusivity Expiration: | 2002 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1997 |
U.S. Biosimilars Launchability Year: | 2022 |
U.S. Biobetters Launchability Year: | 2022 |
Biosimilars/biobetters-related EU Patents: | 2003, based on EP 0108128, apparently equivalent to U.S. patents cited by Intermune; Actimmune has not received centralized EU approval (country-by-country) |
EU Patent Expiration Year: | 2003 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2003 |
EU Biobetters Launchability Year: | 2003 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
Interferon, Human Fibroblast (Gb-23-902-531), Second International Standard
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
K-12, Escherichia coli (E. coli)
HLA-DR bioassay
mannitol
polysorbate 20 (Tween 20)
sodium succinate
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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