Status - approved; marketed

Organizations involved:

Prometheus Inc. – USA mark.

Chiron Corp. – former

Novartis AG – Manuf.;. R&D; Tech.; Parent

Cetus Corp. – R&D; Tech.; Former

Immunex Corp. – R&D; Tech.

Hoffmann-La Roche Ltd. – R&D; Tech.; Patent dispute; Europe mark.

Hyup Jin Corp. – Asia mark.

Ajinomoto Co. Ltd. – R&D; Tech.; Patent dispute; Asia mark.

Immunex Corp. – R&D; Tech.

Sloan-Kettering Mem. Cancer Inst. – R&D; Tech.

Amgen Inc. – Tech.; Patent dispute

Ligand Pharmaceuticals Inc. – Canada mark.

Orion Pharma – Europe mark.

Tecnofarma – Latin Amer. mark.

Key Oncologics (Pty) Ltd. – S. Africa mark.

Cross ref.: See also other interleukin-2 related products: Basiliximab (Simulect; IL-2 receptor monoclonal antibody); Daclizumab (Zenapax; IL-2 receptor monoclonal antibody); and Denileukin diftitox (ONTAK; IL-2/diphtheria toxin fusion protein).

Description: Proleukin is a lyophilized (freeze-dried) formulation of aldesleukin, a recombinant mutein (modified form) of human interleukin-2 (IL-2) expressed by a transformed Escherichia coli (E. coli) bacterial cell line. Aldesleukin or des-alanyl-1, serine-125 interleukin-2 is a non-glycosylated protein with a sequence homologous to human IL-2, except for a serine substituted for cysteine at amino acid position 125 and the N-terminal alanine residue has been deleted. Also, unlike human IL-2, aldesleukin is not glycosylated (since it is expressed by bacteria). Aldesleukin is a hydrophobic protein with a molecular weight of ~15,600 daltons (~15.6 kDa) and a molecular formula is C690-H1115-N177-O203-S6. IL-2, formerly called T-cell growth factor, is a lymphokine normally produced by stimulated T-cells (T lymphocytes). In vivo, IL-2 and aldesleukin result in increased production of various other cytokines and act as immune stimulants. Aldesleukin is very commonly simply referred to as interleukin-2 (IL-2).

After reconstitution (dissolution of the lyophilized powder), aldesleukin exists as biologically active, non-covalently bound microaggregates with an average size of 27 aldesleukin molecules, with sodium dodecyl sulfate (SDS) used as a stabilizing agent. This aggregation state of aldesleukin is likely different from that of native human IL-2. The manufacturing process involves fermentation in a defined medium containing tetracycline hydrochloride, but this antibiotic is not detectable in the final product.

Biological potency of Proleukin is determined by a lymphocyte proliferation bioassay and is expressed in International Units (IU) as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is: 18 million IU (18 MIU) aldesleukin = 1.1 mg protein.

Proleukin is packaged as a sterile, white to off-white, lyophilized cake in single-use vials for intravenous administration. Proleukin is sold in packs of ten vials. Each vial contains 22 million IU of aldesleukin, equivalent to 1.3 mg. When reconstituted with 1.2 mL Sterile Water for Injection, USP, one mL contains 18 million IU (1.1 mg) aldesleukin, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). After reconstitution, aldesleukin is generally diluted in 50 ml of 5% Dextrose Injection, USP, prior to infusion. Proleukin contains no preservatives. Proleukin is stored at 2-8˚C (refrigerated) with a shelf life of 18 months.

Nomenclature: Interleukin-2, rDNA/Chiron [BIO]; Proleukin [TR]; Aldesleukin [USAN INN BAN]; 2-133-interleukin 2 (human reduced), 125-L-serine- [CAS]; 125-L-serine-2-133-interleukin 2 (human reduced) [CAS]; 110942-02-4 [CAS RN]; 85898-30-2 [for human IL-2]; IL-2 [SY]; des-alanyl-1, serine-125 human interleukin-2 [SY]; interleukin-2 (recombinant human) [SY]; T-cell growth factor [SY]; TCGF [SY]; Thymocyte stimulating factor [SY]; Lymphocyte mitogenic factor [SY]; Macrolin [TR in France, perhaps other European countries]; Leuferon-2 [TR in Europe]; NSC 373364 [SY NCI]; NSC 600664 [SY NCI]; NDC 59005-991-01 [NDC]

Interleukin-2 (IL-2) is commonly used ambiguously or erroneously to refer to aldesleukin (the active protein) and/or Proleukin (the formulated product).

Biological.: Human IL-2 is a single chain glycoprotein with 133 amino acid residues and a molecular weight ranging from 15 to 20 kDa depending on the amount of glycosylation. Human IL-2 is O-glycosylated at threonine at position 3. Variants of native human IL-2 with different molecular masses and charges are due to variable glycosylation. Non-glycosylated mutant forms of IL-2, such as aldesleukin, are also biologically active. Glycosylation appears to promote elimination by hepatocytes, with non-glycosylated forms having a longer half-life (desirable for therapeutic uses). The human IL-2 gene contains four exons and maps to human chromosome 4q26-28 (murine chromosome 3). Human IL-2 is expressed as a precursor protein of 153 amino acids with the first 20 amino-terminal amino acids functioning as a hydrophobic secretory signal sequence, which is subsequently cleaved. IL-2 contains a single disulfide bond (positions Cys58/105), which is essential for biological activity.

IL-2 is a lymphokine or cytokine normally produced by T-cells (T lymphocytes), and has an important role in immune system regulation. Under physiological conditions IL-2 is produced mainly by T-cells expressing the surface antigen CD4, i.e., CD4+ T-cells, following their activation by mitogens or allogens. IL-2 initiates its effects by binding to a high affinity heterotrimeric cellular receptor (composed of three subunits known as alpha, beta & gamma with molecular masses of 55, 75 and 64 kDa respectively). The IL-2 receptor is found on a whole range of immune cells such as T- and B-lymphocytes, natural killer cells, monocytes, macrophages, oligodendrocytes and lymphokine activated killer (LAK) cells. The biological activities of IL-2 are mediated by the membrane receptor that is expressed almost exclusively on activated, but not on resting, T-cells at densities of 4-12 x 103 receptors/cell. Activated B-cells and resting mononuclear leukocytes rarely express this receptor. The expression of human IL-2 receptor is modulated by IL-5 and IL-6.

Aldesleukin has been shown to possess immunological activities similar to those observed with native human IL-2: growth and activation of T lymphocytes; induction of natural killer (NK) cell activity; induction of lymphokine activated killer (LAK) cell activity; and potentiation of release of interferon gamma, and B-cell growth factor and cellular differentiation factors. Aldesleukin has been shown in a number of in vitro and animal studies to have activities similar to that of native IL-2.

IL-2 plays a central role in the regulation of immune system functions including the activation and proliferation of lymphocytes of various types. Early studies in murine tumor systems demonstrated the potential of native IL-2 as an anticancer agent. After administration, widespread lymphoid cell proliferation is observed, which is dependent on both dose level and duration of treatment. With prolonged treatment, infiltrating immune cells can be identified in nearly all major organ systems. In vivo administration of aldesleukin produces multiple immunological effects in a dose dependent manner, including activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor (TNF), IL-1 and interferon gamma.

Pharmacokinetic studies have shown that about 30% of aldesleukin administered by intravenous infusion distributes initially to the plasma. Aldesleukin in plasma is primarily cleared by metabolism to amino acids in the cells lining the proximal convoluted tubules of the kidneys. Studies with IL-2 and aldesleukin with and without sodium dodecyl sulfate (SDS) show that preparations with SDS have better biodistribution to various organs, with monomeric IL-2 lacking SDS distributing primarily to the kidneys. The alpha half life of aldesleukin in humans is 13.8 minutes and the beta half life is 80.1 minutes with rapid distribution throughout the plasma. Aldesleukin (administered as microaggregates with SDS) distributes quite extensively to the liver, the lungs and kidney within the first 30 seconds of infusion.

Biological.: The interleukins were given their name when they were initially identified in 1981 as molecules made by leukocytes which acted upon other leukocytes. This definition is now slightly flawed and the interleukins are somewhat inappropriately named, since most of them do not simply act between leukocytes, but are produced by and act upon a number of non-leukocyte cells as well.

Aldesleukin/Proleukin was originally developed by Cetus Corp. (now Chiron Corp.) Based on the animal studies demonstrating anti-tumor activity of IL-2/aldesleukin, studies in patients with renal cell carcinoma were undertaken. These trials initially used a combination of aldesleukin and lymphokine activated killer (LAK) cells. Initial success with this regimen led to further studies using aldesleukin alone. Rejection and delays by FDA in approval of Proleukin for cancer indications, particularly renal cancer, contributed significantly to the weakening of Cetus’ financial position, leading to its acquisition by Chiron Corp. (located across the street) On July 30, 1990, the Biological Response Modifiers Advisory Committee, FDA, concluded that the application filed by Cetus was inadequate and that additional data (trials) were needed. Cetus, subsequently Chiron, developed data on additional patients and long-term follow-up for patients in the original filing. The committee supported the product’s original approval on Jan. 17, 1992, and aldesleukin from Chiron was approved in 1992 for treatment of metastatic kidney cancer. Novartis AG acquired Chiron in late 2005.

A recombinant form of IL-2 (Leuferon) was also originally under development by Hoffmann-La Roche Inc. (in collaboration with Immunex) for treatment of renal cancer, but the company abandoned this after Cetus encountered problems with FDA approval of IL-2 for renal cancer. [Other large companies, such as Takeda and DuPont, also conducted R&D with various recombinant IL-2 polypeptides, as shown by patents]. Roche later licensed Proleukin and markets it as Leuferon-2 in its European territories.

Aldesleukin was one of the first agents to be studied for treatment of HIV-infection and AIDS. In 1982, even before HIV was isolated and linked to AIDS, in vitro studies indicated its potential efficacy, and the National Institutes of Allergy and Infectious Diseases (NIAID), NIH, began clinical trials in 1983. Intermittent subcutaneous IL-2 injections of doses much lower than used for cancer treatment were eventually adopted for testing in HIV patients (to minimize adverse effects), and showed indications: of efficacy in trials. In Oct. 2002, Chiron halted its Phase III trial with Proleukin for HIV (ie., abandoned Proleukin for this indication). Subsequently, the study investigators have continued the trial with funding from NIAID.

Companies.: Proleukin was developed by Cetus Corp., later by Chiron Corp., which acquired Cetus (located across the street from Chiron). Novartis AG acquired Chiron in Oct. 2005. Proleukin is manufactured and marketed in the U.S. by Chiron Corp., CBER/FDA est. no. 1106. Chiron’s establishment license (ELA) was modified on May 5, 1992 (with approval of Proleukin) to include facilities then leased from Cetus Corp. at 1400 53rd Street, Emeryville, CA. The product is now manufactured in Novartis' microbial manufacturing facility in Oceanside, CA.

In Jan. 2010, Prometheus acquired exclusive rights to distribute, promote and sell Proleukin in the U.S. Novartis receives royalties based on sales. The agreement also has options for Promethius to assume worldwide marketing.

Hoffmann-La Roche Ltd. co-markets Proleukin (as Leuferon-2) with Chiron in most of the European Union and Switzerland. Proleukin is marketed by Ligand Pharmaceuticals Inc. in Canada for metastatic renal cell carcinoma treatment. Marketing rights in Scandinavian countries, the Netherlands, France, Italy, Spain, Germany, U.K., and former USSR are held by Orion Pharma. Latin American marketing rights are held by Tecnofarma. Hyup Jin Corp. has exclusively South Korean marketing rights. Key Oncologics (Pty) Ltd. markets Proleukin in South Africa.

Manufacture: A Master Cell Stock consisting of E. coli MM 294-1/pLW 45 is stored in sterile cryotubes in liquid nitrogen. The E. coli K12/MM294-1 cell line carrying plasmid pLW45 (ATCC No. 39,626) is described in U.S. patent 4,530,787 assigned to Cetus (now Chiron). Working Cell Stock of E. coli (used for manufacture) is prepared by fermentation of thawed Master Cell Stock.

Cells from the Working Cell Stock are cultured. The culture is harvested and aldesleukin is extracted into a buffered solution containing sodium dodecyl sulfate (SDS). After a series of steps involving reduction, size exclusion chromatography, and oxidation, the protein is further purified by large-scale reversed phase high performance liquid chromatography (RP-HPLC), and concentrated by precipitation. Aldesleukin is oxidized using o-iodosobenzoic acid solution, so that its cysteine residues are bridged to form cystines (as described by U.S. 4,530,787, assigned to Cetus/Chiron). The resulting paste is stabilized with 1.1% sodium dodecyl sulfate (SDS) solution. After further purification by size exclusion chromatography, the purified protein solution is diafiltered at physiological pH to reduce the SDS concentration. Mannitol and phosphate buffers are added to adjust the concentration of aldesleukin. This formulated product is sterile filtered, aseptically filled into glass vials, and lyophilized (freeze-dried). [Purification and formulation are also described in Example III and other sections of U.S. patent 4,748,234].

An example in U.S. patent 4,748,245, assigned to Cetus/Chiron, describes 1,000 liter scale manufacture of aldesleukin. Cultures were concentrated by cross-flow filtration using a spiral cartridge. Cells were disrupted by three passes through a disrupter at about 6500 psi. After diafiltration versus deionized water, EDTA was added to a final concentration of 2 mM. To ensure that no viable recombinant organisms remained before containment was broken, 1 L of octanol was also added to the fermenter. After several hours, the diafiltered disruptate was again disrupted by one pass through the disrupter. Sucrose was added to the disruptate to give a final density between 1.1 and 1.25 g/mL. The mixture was centrifuged at 10,000-20,000 g’s. A temperature of at least 20˚C was maintained prior to and during centrifugation. The resulting pellet containing purified refractile body particles (containing recombinant protein) was stored as a frozen paste at -80˚C.

A number of assays are used to characterize each lot of aldesleukin and ensure product quality and consistency. The amino acid sequence of aldesleukin has been verified by tryptic peptide map analysis and N-terminal sequencing, and each production lot is monitored for identity by these two methods. Purity is analyzed by non-reducing and reducing SDS-polyacrylamide gel electrophoresis (SDS-PAGE), RP-HPLC, and isolectric focusing. Potency is assayed using a lymphocyte proliferation bioassay using a potency standard which has been referenced against the World Health Organization (WHO) 1st International Standard for IL-2, and expressed in International Units (IU) as defined by that standard. Each lot also must pass tests for sterility, general safety, LAL bacterial endotoxin, plasmid DNA, and host E. coli antigen. The amount of pelletable protein is assayed by centrifugation. A turbidimetric analysis is used to determine the mean size of aldesleukin microaggregates in solution (prior to lyophilization) and must fall within preset specifications to ensure consistency. As a result of variation in diafiltration, final lots of aldesleukin may vary in sodium dodecyl sulfate (SDS) concentration within an acceptance range (set at 160-190 µg/mg protein).

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 = 19920505, first approval, PLA ref. no. 88-659 and 88-66; orphan designation (expired 5/1999); Indication = for the treatment of adults (≥ 18 years old) with metastatic renal cell carcinoma

Date = 19980109; BLA supplement [PLA/ELA converted to BLA 103293]; orphan designation (expires 10/2005); Indication = for use in adults with metastatic melanoma and updated response data for metastatic carcinoma patients, as well as revised package insert information

Date = 20110719, BLA supplement; Indication = addition of new safety information to the package insert that includes a new PRECAUTIONS subsection entitled “Serious Manifestations of Eosinophilia” and updates the ADVERSE REACTIONS, Post Marketing Experience subsection to include eosinophilia.

Date = 20111216, BLA supplement; Indication = modified the ADVERSE REACTIONS, Post Marketing Experience ‘Blood and lymphatic system’ subsection of the package insert to add the term ‘lymphocytopenia’.

Date = 20120712, BLA supplement; Indication = label modified to include information on the effect of antibody formation on the pharmacokinetics of aldesleukin.

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

PROLEUKIN (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).

PROLEUKIN is indicated for the treatment of adults with metastatic melanoma.

Careful patient selection is mandatory prior to the administration of PROLEUKIN. See “CONTRAindications:”, “WARNINGS” and “PRECAUTIONS” sections regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests.

Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS) at treatment initiation respond better to PROLEUKIN, with a higher response rate and lower toxicity (See “CLINICAL PHARMACOLOGY” section, “Clinical Experience” subsection and “ADVERSE REACTIONS” section). Therefore, selection of patients for treatment should include assessment of performance status. Experience in patients with ECOG PS >1 is extremely limited.

Status: Proleukin is the only therapy FDA-approved for the treatment of metastatic renal cell carcinoma (kidney cancer), and was the first therapy approved for the treatment of metastatic melanoma (skin cancer) in 20 years.

On July 30, 1999, Chiron filed a supplement to its existing license (BLA; having been converted from a PLA) for Proleukin to comply with an ongoing FDA post-marketing commitment. This included updated survival data that reinforced the long-term benefit of Proleukin for some patients. The data showed that administering Proleukin can extend cancer-free survival more than 10 years without further treatment in some patients with metastatic kidney cancer or melanoma.

Chiron’s establishment license (no. 1106) was modified on May 5, 1992 (with approval of Proleukin) to include Cetus facilities (across the street).

In Nov. 2004, Maxim Pharmaceuticals Inc. withdrew its NDA filing for approval of its immune modulator drug, Ceplene (histamine dihydrochloride), as a adjuvant in combination with Proleukin for treatment of advanced metastatic malignant melanoma. Its Phase III trial (M0104), the combination failed to reach its primary endpoint of improved overall survival vs. IL-2 alone, and the company received a non-approvable letter from FDA stating another Phase III is required.. Maxim now plans to file for U.S. and European Union approval for Ceplene plus Proleukin for treatment of acute myeloid leukemia (AML), for which a Phase III trial has been completed.

No centralized EU approval has been granted.

Tech. transfer: Chiron holds various IL-2/aldesleukin patents, including U.S. 5,037,644 originally filed by Cetus Corp. U.S. patents cited on the product insert are RE33,653; 4,530,787; 4,569,790; 4,604,377; 4,748,234; 4,572,798; 4,959,314; and 5,464,939. Other related U.S. patents held by Chiron include 4,752,585 and 4,853,332.

IL-2 was initially made by cultivating stimulated human peripheral blood lymphocytes (PBL) or other IL-2-producing cell lines. See, for example, U.S. Pat. No. 4,401,756, assigned to Immunex Corp. Immunex had licensing agreements with Ajinomoto Co. Ltd. for commercialization of IL-2 in Japan, Korea and Taiwan. Immunex’s rights to IL-2 originated from production of substantially pure native human IL-2 from cell cultures of malignant T-cells, e.g., see Gillis, et al., U.S. patent 4,473,642, assigned to Immunex Corp. U.S. patent 4,401,756, “Process for preparing human interleukin 2,” Gillis, S., August 30, 1983, assigned to Immunex Corp., covers the process for preparing IL-2, originally reported by Gillis et al. in “Biochemical and Biological Characterization of Lymphocyte Regulatory Molecules V. Identification of an Interleukin 2-Producing Human Leukemia T Cell Line,” Journal of Experimental Medicine, 1980. This involved culturing malignant neoplastic cells, such as human leukemia and lymphoma cells, and their stimulation by a T-cell mitogen (e.g., phorbol myristate acetate), producing a supernate containing IL-2, followed by purification. Use of the Jurkat-FHCRC leukemic human T cell line in a culture medium composed of Click’s medium together with certain additives and a plant mitogen, such as PHA, produced between 100 to 300 times the amount of human IL-2 per milliliter than previously generated by lectin stimulation of identical numbers of human peripheral blood lymphocytes.

Hoffmann-La Roche Inc. and the Sloan Kettering Cancer Center were involved in a patent dispute with Cetus concerning patents for purified homogeneous IL-2. Roche held a U.S. patent application assigned to Sloan Kettering concerning purified natural IL-2 and rights to patents licensed from Ajinomoto Ltd. concerning recombinant IL-2 (e.g., U.S. 4,738,927), while Cetus held patents concerning IL-2 muteins, e.g., aldesleukin, and recombinant manufacturing processes. At the time, Roche was in early stages of developing a IL-2 product and a pegylated IL-2 in collaboration with Immunex Corp. A settlement was concluded in late 1988 with both Cetus and Roche cross-licensing non-exclusive rights for their respective IL-2 patent portfolios (including their licensed patents), while Cetus retained full rights to IL-2 muteins (including aldesleukin). As part of the agreement, Roche (and presumably also Sloan Kettering) and Immunex (now Amgen) receive unspecified royalties from Cetus (now Chiron/Novartis).

Cetus Corp. and Amgen Inc. settled a patent dispute in 1988 concerning recombinant IL-2/aldesleukin, with Amgen assigning all U.S. and international rights to Cetus and each company retaining rights to independently develop, manufacture and market IL-2 products royalty free (except in the U.S.). Ortho Pharmaceutical, a subsidiary of Johnson & Johnson Co., had licensed U.S. patent rights from Amgen, but never developed an IL-2 product.

U.S. patent RE33,653, “Human recombinant interleukin-2 muteins,” Mark, et al., July 30, 1991, assigned to Chiron, (and also 4,518,584), describes IL-2 muteins including aldesleukin. The muteins are made via bacterial expression of mutant genes that encode the muteins that have been synthesized from the genes for human IL-2 by oligonucleotide-directed mutagenesis. Based on time during FDA review (under 35 USC §156), the expiration date for this patent was extended from Oct. 19, 2002, to May 5, 2006 (897 days). This is the only Proleukin-related patent for which a patent extension has been granted.

U.S. patent 4,959,314, “Cysteine-depleted muteins of biologically active proteins,” Sept. 25, 1990, assigned to Chiron, concerns IL-2 muteins (including aldesleukin) in which cysteine residues not essential to biological activity have been deleted or replaced with other amino acids to eliminate sites for intermolecular crosslinking or incorrect intramolecular disulfide bridge formation.

U.S. 5,614,185, “Compositions Containing Reduced, Microbially Produced Interleukin-2 (IL-2),” March 25, 1997, assigned to Chiron Corp., describes various aspects of the manufacturing of IL-2.

E. coli K12/MM294-1 cells carrying plasmid pLW45 (ATCC No. 39,626) used for manufacture of aldesleukin are described in U.S. 4,530,787 assigned to Cetus Corp.

U.S. patent 4,748,234, “Process for recovering refractile bodies containing heterologous proteins from microbial hosts,” assigned to Cetus (Chiron), May 31, 1988, broadly covers aspects of the isolation and purification of recombinant proteins including IL-2. Expressed proteins are recovered from bacterial, e.g., E.coli, refractile materials (inclusion bodies; refractile bodies) containing expressed recombinant protein. One recovery process involves disrupting the cell wall and membrane of the host cell (E. coli), removing greater than 99% by weight of the salts from the disruptate, redisrupting the desalted disruptate, adding a material to create a density or viscosity gradient in the liquid within the disruptate, and separating the refractile bodies from the cellular debris by high-speed centrifugation. A version of this recovery process involves salt removal by diafiltration.

Trials: In Jan. 2003, Chiron halted sponsorship of a large international Phase III clinical trial (SILCAAT) with Proleukin for treatment of HIV-infection. This 100-site, 1,400 patient trial was among the few advanced-stage trials using an immune stimulant/modulator for treatment of HIV-infection and based on clinical, e.g., disease advancement, rather than surrogate markers, e.g., viral load. However, the trial is continuing with funding from the National Institute of Allergy and Infectious Diseases (NIAID), NIH.

Medical: For both of its approved cancer indications:, Proleukin is administered by a 15-minute, 600,000 IU/kg (0.037 mg/kg), intravenous (IV) infusion every 8 hours for five days. This is followed by a 9-day “rest period,” followed by start of another 5-days of treatment period (followed by 9 days of rest). The two cycles of treatment constitute a course of treatment with Proleukin, during which patients receive a maximum of 28 infusions. Patients are hospitalized during treatment, but can go home during the rest period. After about 2 months of treatment, patients are examined to determine whether their tumors have shrunk. Patients whose tumors have shrunk receive an average of 2 treatment courses, depending upon the success of the first course and the patient’s state of health. Nonresponds may receive further courses of treatment.

Unlike many therapeutics, side effects from Proleukin are not managed by reducing the amount given, rather treatment is halted temporarily until the side effects subside, and therapy can then be resumed. Proleukin use is restricted to patients with normal cardiac and pulmonary functions, as defined by thallium stress testing and formal pulmonary function testing. Proleukin administration is associated with capillary leak syndrome (CLS), characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. Proleukin is also associated with impaired neutrophil function (reduced chemotaxis), and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Due to its adverse effects, most (>90% in some trials) patients do not receive all of their scheduled infusions during each course of treatment.

Disease: An estimated 11,900 persons in the U.S. die annually from metastatic kidney cancer (renal cell carcinoma; RCC), with about 31,900 new cases/year. About 20% of RCC patients are eligible for high-dose Proleukin. For some of these patients, treatment can evoke an immune response that completely eradicates the tumor for over 15 years. The majority of patients are between the ages 50-70 when diagnosed. Kidney cancer is twice as common in men as women.

Market: Total 2010 worldwide sales are estimated to be $200 million.

The 2006 world market for IL-2 (Proleukin) was reported to be $213 million. It appeared that Roche’s sales are on the order of 60% of that of Chiron.

In Jan. 2010, it was reported that Proleukin U.S. sales were $75 million, and based on this it is crudely estimated that total annual revenue is about $125 million. Total revenue/sales of Proleukin reported by Chiron were $124 million in 2005; $129 million in 2004; $115 million in 2003, $114 million in 2002, $93 million in 2001, $113 million in 2000, $112 million in 1999, $93 million in 1998, $71 million in 1997, $64 million in 1996, $55 million in 1995, $46 million in 1994, and $43 million in 1993. Chiron/Novartis has not reported 2006 sales, but they are likely much the same as recent years.

The 2007 Average Wholesale Price (AWP) is $901.54/vial (Red Book, 2007). The AWP was $868.13/vial in 2005, and ($811.50 in 2004.

Based on the AWP, a single course of treatment, 28 infusions of 600,000 IU/kg (0.037 mg/kg; 3.0 million IU each) for a 50 kg (110 lb.) patient would involve 28 infusions of 30 million IU, a total of 840 million IU, requiring 39 22-million IU vials, costing ~$35,160.

In Oct. 2003, the Centers for Medicare and Medicaid Services (CMS) implemented a change in the Medicare reimbursement code for high-dose Proleukin. This particularly benefited patients with metastatic renal cell carcinoma (RCC; kidney cancer) for which Proleukin is the only FDA-approved treatment. Prior to the change, only about one-third of the cost of Proleukin was reimbursed, and some hospitals had stopped offering high-dose IL-2 because of its high costs and inadequate reimbursement. Recognized as a unique therapeutic, CMS now covers ~88% of the cost (AWP) of Proleukin.

R&D: Proleukin has been studied in trials in combination with Rituxan (see CD20 Mab, rDNA entry) in patients with low-grade non-Hodgkin’s lymphoma having failed on Rituxan, and in patients with high-grade lymphoma having failed chemotherapy and/or on Rituxan. A Phase I study tested Rituxan in combination with liquid Proleukin, a new formulation designed for subcutaneous administration, in patients with advanced non-Hodgkin’s lymphoma. Results were reported in Jan. 2004, and Chiron reported it would not advance trials for this combination.

In May 2004, Maxim Pharmaceuticals reported positive results from a Phase III trial of Proleukin in combination with Ceplene (a histamine salt), an immune stimulant, for treatment of acute myeloid leukemia (AML), meeting the primary endpoint of improving survival.

R&D: Companies have already started development of biogeneric (biosimilar, biocomparable, follow-on protein, follow-on biologic, etc.) versions of Proleukin. For example, PharmaSelect has licensed biogeneric IL-2 manufactured by Shenyang Sunshine Pharmaceutical (PRC) for commercialization in Europe and other territories.

In May 2004, Biomira Inc. and Inno-Centre Alberta formed a spin-off company, Oncodigm BioPharma Inc., for the development of Liposomal-Interleukin-2 (L-IL-2), involving liposomal encapsulation of a IL-2 mutein, projected to reenter clinical trials in 2005. Biomira had previously suspended trials to concentrate on other products.

Rhein Biotech, now merged into Dynavax Technologies Corp., is developing a recombinant yeast (Hansenula polymorpha) expressed IL-2 product manufactured by its PC Gen S.A. subsidiary in Argentina. The product will be marketed as a biogeneric (biosimilar, biocomparable, follow-on, or other generic biopharmaceutical) in countries where lack of patent protection for Proleukin allows.

Vical, Inc. is developing an IL-2 gene therapy involving direct injection into a tumor lesion of plasmid DNA encoding IL-2 followed by electroporation. The pDNA is designed to result in localized expression of high levels of IL-2 protein and stimulation of the immune system to attack the tumor without Proleukin’s systemic toxicities. A Phase I trial began in July 2005.

Transgene S.A. is developing an attenuated MVA vaccinia virus vector encoding the Muc1 tumor-associated antigen and IL-2 genes, now in Phase IIb trials for non-small cell lung cancer (NSCLC).