Status - approved; marketed

Organizations involved:

Amgen, Inc. – Manuf. (formerly); R&D; Tech.

Swedish Orphan Biovitrum AB (Sobi) – World mark.

NPS Pharmaceuticals, Inc. – USA mark.

Boehringer Ingelheim Pharma KG - Manuf.

Synergen Inc. – R&D; Tech.; Former inv.

University of Colorado – R&D; Tech.

Columbia University – Tech.; Patent dispute

Ariad Pharmaceuticals, Inc. – Patent dispute

Megapharm Ltd. – Israel mark.

Cross ref.: See also the entries for the TNF antagonists approved for treatment of rheumatoid arthritis – infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira).

Description: Kineret is an aqueous formulation of anakinra, a recombinant N-methionyl human interleukin-1 receptor antagonist (N-met-IL-1ra; met-IL-1ra) nonglycosylated protein expressed in Escherichia coli (E. coli) bacteria. met-IL-1ra differs from native human interleukin-1 receptor antagonist (IL-1ra) by the addition of a single methionine (Met) residue at its amino terminus (an N-terminal secretion leader sequence from expression in E. coli cells). N-met-IL-1ra consists of 153 amino acids and has a molecular weight of 17.3 kDa. The molecule blocks the biologic activity of the cytokine interleukin-1 (IL-1) by competitively inhibiting IL-1 from binding to the cellular IL-1 type I receptor. IL-1 has a broad range of activities including cartilage degradation and stimulation of bone resorption.

Kineret is supplied as a preservative free solution in single use 1 mL prefilled glass syringes for daily subcutaneous (SC) administration. Each 1 mL syringe contains: 0.67 mL (100 mg) of anakinra (N-met-IL-1ra) in a solution (pH 6.5) containing sodium citrate (1.29 mg), sodium chloride (5.48 mg), disodium ethylenediaminetetraacetic acid (EDTA) (0.12 mg), and polysorbate 80 (Tween 80; 0.70 mg) in Water for Injection, USP. Kineret is stored 2-8°C (refrigerated), with the expiration date on its label (with no specific time period reported in the product insert). The date of manufacture is the date of final sterile filtration of the formulated product.

Nomenclature: Interleukin-1ra, rDNA [BIO]; Kineret [TR]; Antril [TR; former for sepsis indication]; Anakinra [FDA]; interleukin-1 receptor antagonist [SY]; IL-1ra [SY]; interleukin-1 inhibitor [SY]; IL-1i [SY]; met-IL-1ra, rDNA [SY]; IL-1 receptor antagonist protein [SY]; IRAP [SY]; NDC 55513-177-07 and NDC 55513-177-28 [NDC]

Following conventions used by Amgen, “anakinra” or met-IL-1Ra is generally used to refer to the active ingredient, although this term (like “Kineret”) is also often used to also refer to the formulated product.

Biological.: Interleukin 1 (IL-1) refers to two human proteins (IL-1alpha and IL-1beta) with a key role early in the inflammatory response. Both proteins are made as 31 kDa intracellular precursor proteins which are cleaved upon secretion to yield biologically active carboxy-terminal 17 kDa fragments. The IL-1 proteins are potent inflammatory and pyrogenic cytokines that normally have beneficial effects, but that can also have extremely harmful effects. For example, IL-1 proteins are involved as mediators that provoke damage to tissues, e.g., in rheumatoid arthritis (RA).

The two IL-1 proteins bind to cell surface receptors found on almost all cell types and trigger a range of responses either alone or in concert with other secreted factors, including inflammatory cytokine induction (e.g., of TNF, IL-8) and the secretion of degradative enzymes (e.g., collagenase). IL-1 activates transcription factors such as NF-kappaB and AP-1. IL-1 stimulates the production of prostaglandin E2 (PGE2), and cyclooxygenase, which account for much of the inflammation associated with RA. IL-1alpha, IL-1beta and tumor necrosis factor (TNF) share several biologic actions. IL-1 and TNF-alpha induce the production of each other, and they act synergistically. IL-1 also stimulates osteoclasts, resulting in bone resorption. Several of the activities of IL-1 on target cells are believed to be mediated through activation of kinase cascades that have also been associated with cellular stress, such as the stress-activated MAP kinases JNK/SAPK and p38.

A third member of the human IL-1 protein family, IL-1 receptor antagonist (IL-1ra), was discovered later. IL-1ra is an endogenous acute-phase antiinflammatory protein. IL-1ra acts as a natural antagonist of IL-1 (IL-1alpha and IL-1beta) by binding to the cellular IL-1 type I receptor. This prevents the IL-1 proteins from binding to the receptor. However, unlike IL-1alpha and IL-1beta, IL-1ra does not transduce an intracellular signal or a biological response. IL-1ra has no biological activity, other than antagonizing the activity of IL-1 by binding to IL-1 receptor. IL-1 was the first (and may still be the only) cytokine for which an antagonist polypeptide for the receptor (IL-1ra) has been described.

The first observation of IL-1 inhibition by the IL-1ra occurred in the lab of Dr. William Arend, CU-Health Sciences Center.

The objective for Kineret therapy is to occupy enough IL-1 cellular receptors with N-met-IL-1ra to block binding by IL-1alpha and IL-1beta to the receptors. In vitro, over 95% receptor occupancy by IL-1ra is required to effectively block IL-1 signaling.

All three IL-1 proteins (IL-1alpha, IL-1beta and IL-1ra) share 25-30% amino acid identity and a similar three-dimensional structure consisting of twelve beta-strands folded into a beta-barrel, with an internal 3-times repeated structural motif. IL-1ra production may be induced in various human cells, including mononuclear phagocytes, polymorphonuclear cells, and fibroblasts, by cytokines, immunoglobulin G (IgG), and bacterial products.

Anakinra is well absorbed following subcutaneous injection, with an in vivo half-life of about 4-6 hours. The assay used to measure IL-1 inhibitor activity is based on that described in Biochem. Biophys. Res. Comm. 154: 1189-1196. 1988, based on prolonged exposure to IL-1 being cytotoxic to the human melanoma cell line A375.

Companies.: Anakinra (as Antril) was originally developed by Synergen Inc. for treatment of severe sepsis (septic shock). In July 1994, Synergen abandoned development after Antril failed to show statistical significance for improving mortality in a Phase III trial. Development of Antril by Synergen was at least partially funding through Synergen Clinical Partners, L.P. Amgen Inc. obtained Antril through its acquisition of Synergen Inc. (after the failure of Antril for sepsis).

Kineret was developed and is manufactured by Amgen Inc., CBER/FDA est. no. 1080, at is LakeCenter, CO, facilities near Boulder. Kineret was originally marketed in the U.S. by Amgen, later by NPS Pharmaceuticals, Inc., with Biovitrum AB [now renamed Swedish Orphan Biovitrum AB (Sobi)]and Amgen co-promoting Kineret in certain European Union and Nordic countries.

In Aug. 2004, Amgen granted NPS Pharmaceuticals, Inc. rights for U.S. marketing/promotion of Kineret to rheumatologists. Amgen supplies product, materials and support to NPS, which promotes Kineret and receives a percentage of incremental Kineret revenues. NPS had its own trained sales representatives in the field to detail Kineret to physicians in the first quarter of 2005. This arrangment was expected to facilitate NPS developing a U.S. sales for Preos (parathyroid hormone, rDNA) upon its approval for osteoporosis.

In Sept. 2008, Amgen granted Biovitrum AB (now SOBI) a worldwide exclusive license to Kineret for its current approved indication (rheumatoid arthritis).

In July 2009, Biovitrum licensed marketing rights in Israel to Megapharm.Ltd.

In Nov. 2009, Amgen granted Biovitrum AB a worldwide exclusive license to Kineret for certain orphan indications:.

In June 2013, SOBI announced sBLA approval of Boehringer Ingelheim GmbH's microbial site in Vienna, Austria, for manufacture of anakinra, with manufacturing to be transferred to BI from Amgen.

In Sept,. 2013, SOBI acquired the full rights to develop and commercialize Kineret (anakinra) from Amgen for all therapeutic indications. The revised agreement built on the previous agreement that gave Sobi rights for Kineret within the field of Rheumatoid arthritis (RA) and four orphan drug indications, including Cryopyrin Associated Periodic Syndrome (CAPS).

Manufacture: Anakinra is manufactured by conventional fermentation of recombinant E. coli bacteria transformed with the gene for human IL-1ra. As described in U.S. patent 5,453,490, assigned to Synergen, Inc., preferred methods for production of commercial quantities of IL-1ra include fermentation of E. coli transformed with a plasmid containing DNA encoding IL-1ra, e.g., plasmid pDD6 transformation of E. coli JM107 to yield the production strain SGE90 capable of expressing >50 grams of highly purified IL-1ra per 100 liters of fermentation broth (in a 1,600 L fermentor). This is followed by cell processing, including cell recovery, lysis, and clarification of the lysates; a first ion exchange chromatography step using a column filled with a cation exchange resin, S-Sepharose; a second ion exchange chromatography step using an anion exchange resin, Q-Sepharose; and final processing steps including concentration and diafiltration. Quantitative analytical tools used to evaluate yield and purity include reverse phase HPLC (RP-HPLC), ion exchange HPLC (IE-HPLC), an SDS-PAGE assay, a size exclusion assay, trypsin peptide mapping, and assay for biological activity (inhibition of IL-1).

FDA class: Biologic BLA

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

Approvals: Date = 20011114; BLA, first approval

Date = 20030627; BLA supplement; Indication = revise insert/labeling to include information on an increased risk of serious infections when used with Enbrel (etanercept; a tumor necrosis factor inhibitor), and a revised definition of the threshold for neutropenia

Date = 20130108; BLA supplement; Indication = treatment of children and adults with neonatal-onset multisystem inflammatory disease (NOMID)

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

Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents (see WARNINGS).

Status: The BLA was filed in late 1999, and approval was granted on Nov. 14, 2001; approval time = ~2 years. Kineret is exempt from CBER lot release requirements.

In Oct. 2002, Amgen filed a BLA supplement for the use of Kineret to inhibit the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis.

Kineret received European Union (EU) approval in March 2002 for treatment of rheumatoid arthritis in combination with methotrexate in patients refractory to methotrexate alone.

On Jan., 8, 2013, FDA approved Kineret with Orphan Drug designation for the treatment of children and adults with neonatal-onset multisystem inflammatory disease, the most severe form of cryopyrin associated periodic syndromes (CAPS). This is the first approval allowing the use of Kineret in children.

Tech. transfer: Kineret is based on the work of Dr. William Arend, professor of medicine, Rheumatology Division, CU-Denver and Health Sciences Center, University of Colorado. IL-1ra-related patents with Dr. Arend as an inventor include 5,075,222; 6,599,873; and 6,858,409.

Naturally-occurring forms of human IL-1ra are described in 5,075,222, “Interleukin-1 Inhibitor,” assigned to Synergen, Inc. U.S. 6,599,873, ”Interleukin-1 inhibitors, compositions, and methods of treatment,” coassigned to Amgen and the University of Colorado, claims recombinant IL-1ra polypeptides and use for treatment of various diseases. U.S. 6,159,460, assigned to Amgen Inc. describes recombinant IL-1ra and its uses. U.S. 5,453,490, assigned to Synergen, Inc. (now Amgen), describes methods for commercial manufacture of fermentation, isolation, and purification of IL-1ra (several to hundreds of grams of purified product obtained from 100 liters of fermentation broth). U.S. 6,858,409, coassigned to Amgen and the Univ. of Colorado, claims various IL-1 inhibitors.

Amgen 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 again seeking royalties, which Amgen 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).

In May 2006, as discussed in the Tech. transfer section of the Xigris entry (#243), a U.S. District Court for the District of Massachusetts jury ruled in favor of ARIAD Pharmaceuticals in a suit alleging infringement by Xigris (from Lilly) of U.S. 6,410,516, "Nuclear factors associated with transcriptional regulation," assigned to the Massachusetts Institute of Technology (MIT); Whitehead Institute for Biomedical Research; and Harvard University, and exclusively licensed by ARIAD. The application was filed in 1995 but with a priority date of Nov. 13, 1991 and has a calculated expiration data of Jun 25, 2019. . While the specifications hypothesized three types of molecules with the potential to reduce NF-кB activity, the claims were not directed to any specific substance that reduces NF-кB activity. Its original priority date had been in 1986, but the PTO assigned it a new priority date based on discrepancies in the patented subject matter of the various applications. The filing went through 16 years of continuations, restrictions, and abandonments before finally issuing in 2002.

The 6,410,516 patent broadly claims nuclear factor kappa B (NF-kB) and NF-kB inhibitors. Although Kineret does not primarily function as a NF-kB inhibitor, like many therapeutics, including aspirin and Enbrel, it exhibits NF-kB inhibition. A week before this ruling was issued, Amgen filed a preemptive lawsuit against ARIAD seeking a declaratory judgment that Enbrel and Kineret do not infringe Ariad patents. In Sept. 2006, a federal court jury denied this motion. In April 2007, Ariad filed a countersuit against Amgen and Wyeth accusing the companies of patent infringement, citing Enbrel (Amgen and Wyeth) and Kineret (Amgen), but later withdrew Kineret from the suit. Ariad has stated that the claims at issue against Amgen and Wyeth concerning Enbrel and Kineret are different from those found valid and infringed by Lilly (see the Xigris entry).

In July 2007, the U.S. District Court ruled in favor of the plaintiffs (ARIAD and MIT) in their lawsuit against Lilly. The Judge’s opinion found that the patent is valid and enforceable and that judgment may be entered for the plaintiffs in accordance with the prior jury verdict.

In April 2009, a Federal Circuit panel reversed the jury's verdict on written description (ivalidated the patent), holding the asserted claims invalid for lack of an adequate written description as required by 35 U.S.C. § 112, first paragraph. Ariad petitioned for rehearing en banc, challenging the existence of a written description requirement separate from the enablement requirement. In light of the long-running controversy concerning the distinctness and proper role of the written description requirement, the Court granted Ariad’s petition.

On March 22, 2010, the Federal Circuit issued an important en banc decision upholding a separate written description requirement under 35 U.S.C. § 112 (and upholding the patent). The Court rejected the patent owners' contention that the written description requirement is simply a part of the enablement requirement, which requires that the specification teach how to make and use the invention. The Court had received over 25 amicus briefs. This decision kept intact the ability of patent infringement defendants to use the written description requirement to force a narrow construction of broad claims and to invalidate genus claims where the written description is expressly or implicitly limited to a species.

EP 0343684, "Interleukin-1 inhibitors," assigned to Synergen, expired in 2009.

Disease: Arthritis is a chronic joint disease typically characterized at the microscopic level by the inflammation of synovial tissue and by a progressive degradation of the molecular components constituting the joint cartilage and bone. Continued inflammation and erosion of joints frequently lead to considerable pain, swelling, and loss of function. Rheumatoid arthritis (RA) affects more than 2.1 million Americans. While the etiology of arthritis is poorly understood, certain cytokines figure prominently in the mediation of associated inflammation. IL-1 has a broad range of RA-associated activities, including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption.

The involvement of IL-1 in arthritis has been implicated by two distinct lines of evidence: 1) increased levels of IL-1 and of the mRNA encoding it are found in the synovial tissue and fluid of arthritic joints and 2) the administration of IL-1 to healthy joint tissue results in the erosion of cartilage and bone. The levels of naturally occurring IL-1Ra in synovium and synovial fluid of rheumatoid arthritis patients are not sufficient to compete with the elevated amount of locally produced IL-1. This imbalance allows IL-1 to bind to IL-1 receptors at a more aggressive rate and perpetuate proinflammatory responses.

Trials: Pivotal, randomized, double-blinded, placebo-controlled, clinical trials enrolled 2,932 rheumatoid arthritis (RA) patients. More than 2,600 were treated with Kineret. Alone or in combination with other commonly used disease-modifying therapies, e.g., methotrexate, Kineret improved the signs and symptoms of RA. Many clinical responses, including a decrease in inflammation and pain, were seen by the fourth week of treatment and most were seen by week 13. After six months of therapy, 38% of Kineret patients and 22% of placebo patients achieved a 20% improvement in the American College of Rheumatology (ACR) criteria. This involved a 20% improvement in the number of swollen and tender joints, plus a greater than or equal to 20% improvement in at least three of five criteria: physician assessment of disease, patient assessment of disease, pain, C-reactive protein (a marker of inflammation), and health assessment questionnaire. The most common adverse event reported was a mild and transient local injection site reaction that typically lasted 14 to 28 days.

Amgen was conducting U.S. trials of Kineret in combination with tumor necrosis factor (TNF) inhibitors, e.g., Enbrel, even before it acquired Immunex and Enbrel. Amgen hoped that Enbrel and Kineret would offer improved safety and effectiveness for rheumatoid arthritis. In Feb. 2003, a clinical trial showed that combined administration of Enbrel plus Kineret for treatment of rheumatoid arthritis provided no additional therapeutic benefit and resulted in an increased incidence of serious infection and neutropenia compared with Enbrel alone. This was not expected to affect sales of either product, even though labeling for both products was modified to include warnings about their combination.

Medical: The recommended dose of Kineret for the treatment of rheumatoid arthritis is 100 mg (1 vial)/day by subcutaneous injection. Kineret can be used alone or in combination with disease modifying antirheumatic drugs (DMARDs), but not tumor necrosis factor (TNF) antogonists, e.g., Enbrel, Remicade or Humira.

Market: Kineret is minor product for Amgen, and the company has not reported its sales in recent years. Some analysts had originally projected at least $150 million in peak sales annually, once established on the market

Worldwide revenue was $62 million in 2009..

In April 2005, Friedman Billings and Ramsey (FBR) analysts had projected Kineret total sales to be $25 million in 2005; $150 million in 2006; and $275 million in 2007.

The 2007 Average Wholesale Price (AWP) is $51.586/vial ($44.68 in 2004), $361.03 for 7 ($312.73 in 2004); and $1,444.13 for 28 (Red Book, 2007). The 2005 AWP was $46.86/vial ($44.68 in 2004), $328.02 for 7 ($312.73 in 2004); and $1312.08 for 28 ($1,250.93 in 2004).

Enbrel, also from Amgen (previously Immunex/Wyeth), and Remicade from Ortho/Johnson & Johnson had a significant head start in the RA market, and both have shown more impressive effectiveness rates in clinical trials. These are among the main factors restricting the market for Kineret.

In Nov. 2003, The U.K. National Institute for Clinical Excellence (NICE), which sets purchase/reimbursement guidelines for the National Health System (NHS), rejected appeals by Amgen of its July 2003 Final Appraisal Determination (FAD) that Kineret is not as effective as tumor necrosis inhibitors (e.g,. Enbrel, Humira) in relieving the signs and symptoms of rheumatoid arthritis.

In March 2005, NPS launched its own specialty sales force to promote Kineret to U.S. rheumatologists.