Status - approved; marketed

Organizations involved:

Novartis Pharmaceutical Corp. – USA mark.

Novartis AG – Manuf.; R&D; Tech.; Intl. mark.

Sandoz Corp./AG – Former

Cerimon Pharmaceuticals Inc. - World mark.

Seragen Inc. – Former

Ligand Pharmaceuticals Inc. – Tech.

Royalty Pharma, AG – Tech.

University of Glasgow – Tech.

Genentech, Inc. – Tech.

Beth Israel Deaconess Medical Center – R&D; Tech.

Amgen Inc. – Tech.

Cross ref.: See the entry for Monoclonal Antibodies (#300). See also other interleukin-2 related products: aldesleukin (Proleukin; recombinant IL-2); daclizumab (Zenapax; another recombinant IL-2 receptor monoclonal antibody); and denileukin diftitox (Ontak; recombinant IL-2/diphtheria toxin fusion protein). Note, both Simulect and Zenapax involve monoclonal antibodies targeting the same IL-2 receptor subunit.

Description: Simulect is a lyophilized (freeze-dried) formulation of a recombinant chimeric (human-murine) IgG1kappa monoclonal antibody (basiliximab) glycoprotein specifically binding the alpha subunit (p55 alpha; CD25; Tac subunit) of the human high-affinity interleukin-2 receptor (IL-2Ra) expressed on the surface of activated lymphocytes, produced by mammalian cell culture using a transformed murine (mouse) myeloma cell line, apparently NS0 cells. The murine myeloma cell line has been transformed with plasmids containing human heavy and light chain immunoglobulin constant (framework) region genes and murine heavy and light chain variable (antigen-specific) region genes derived from the RFT5 murine monoclonal antibody with binding selectivity for IL-2Ra. Based on the amino acid sequence, the calculated molecular weight of the protein is 144 kDa.

Simulect is packaged in 6 mL vials, each containing 20 mg basiliximab, 7.21 mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate, 1.61 mg sodium chloride, 20 mg sucrose, 80 mg mannitol and 40 mg glycine, to be reconstituted in 5 mL of Sterile Water for Injection, U.S.P., for intravenous infusion. The product contains no preservatives. Simulect is stored at 2-8˚C (36-46˚F; refrigerated).

Simulect does not contain any ingredients derived from animal sources and complies with European Commission Directive 97/534/EC. During purification, multiple steps greatly decrease any contaminating infectious agents, e.g., model viruses are reduced by 12-18 logs.

Biological.: Three different types of IL-2 cellular receptors are distinguished, with each expressed differentially and independently. The high affinity IL-2 receptor (IL-2R), with Kdis =10 pM, constitutes approximately 10% of all IL-2 receptors expressed by T-cells. The high-affinity IL-2R is a membrane receptor complex consisting of the two subunits – IL2R-alpha (Tac antigen; T-cell activation antigen; p55) and IL2R-beta (p75; newer designation is CD122) as the ligand/receptor binding domains and a gamma chain as a signaling component. An intermediate affinity IL-2 receptor (Kdis =100 pM) consists of the IL2R-beta (p75) subunit and a gamma chain, while a low affinity receptor (Kdis =10 nM) is formed by IL2R-alpha (p55) alone. The 219 N-terminal amino acids of the IL2R-alpha (p55; Tac) protein, the target for basiliximab binding, comprise an extracellular (cell surface-exposed) domain (e.g., see Leonard, W., et al., Science, 230, 633-639, 1985).

Basiliximab functions as an IL-2 receptor antagonist by binding with high-affinity to the IL2R-alpha (Tac subunit; p55) portion of the high-affinity IL-2 receptor complex on the surface of activated T lymphocytes (T-cells), e.g., lymphocytes induced by interferon gamma, inhibiting further IL-2 binding. Basiliximab binding is highly specific for IL2R-alpha (Tac), which is expressed only on activated and not resting lymphocytes.

Basiliximab functions as an IL-2 receptor antagonist by binding with high affinity (Ka = 1 x 10-10 M) to the alpha chain of the high affinity IL-2 receptor complex, resulting in inhibition of IL-2 binding to IL-2 receptors on lymphocytes. Basiliximab is specifically targeted against IL-2Ra, which is selectively expressed on the surface of activated, not resting, T lymphocytes (T-cells). This specific high affinity binding to IL-2Ra competitively inhibits binding by IL-2 and IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response, e.g., involved in allograft rejection. In the circulation, basiliximab also impairs the response of the immune system to antigenic challenges, increasing susceptibility to infection.

Administration of Simulect inhibits IL-2-mediated activation and proliferation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection, e.g., tissue transplant rejection. While in the circulation, basiliximab acts as an immune suppressant and impairs the response of the immune system to antigenic challenges. Basiliximab and cyclosporine have complimentary mechanisms of action. Cyclosporine interferes with IL-2 production and blocks T-cell proliferative signals during early phase T-cell activation, but does not inhibit the process completely. Basiliximab targets the IL-2 receptor, binding extensively to the receptor and blocking binding of IL-2, inhibiting IL-2-driven proliferation of activated T-cells. Basiliximab binds with high affinity to IL-2R, and remains bound and blocks the receptor for 4-6 weeks post-transplantation, the critical risk period for acute organ rejection.

Nomenclature: Interleukin-2 receptor Mab, rDNA/Novartis [BIO]; Simulect [TR]; basiliximab [FDA]; anti-(human interleukin 2 receptor) immunoglobulin G1 (human-mouse monoclonal CHI621 alpha1-chain) disulfide with human-mouse monoclonal CHI621 light chain, dimer [CAS]; interleukin-2 (IL-2) receptor monoclonal antibody [SY]; recombinant chimeric (murine/human) monoclonal antibody anti-IL-2Ra [SY]; CD25 monoclonal antibody [SY]; chimeric anti-Tac monoclonal antibody [SY]; SDZ CHI 621 and SDZ-CHI-621 [Sandoz no.]; chRFT5 [SY]; NDC 0078-0393-61; NDC 0078-0331-84 [NDC]

Basiliximab is termed a “chimeric” recombinant monoclonal antibody, while another product targeting the same IL-2 receptor, daclizumab (Zenapax), is a recombinant “humanized” monoclonal antibody. These semantic distinctions are made on the basis of the proportions and structures of the human and murine antibody portions recombined into the recombinant immune globulin molecule and related methods, patents, licensing, and disputes. Chimeric antibodies generally contain larger percentages and portions of murine antibody than do humanized antibodies. See the Monoclonal Antibodies entry (#300) for further information.

Companies.: Simulect was originally developed by Seragen Inc., now a subsidiary of Ligand Pharmaceuticals. Simulect was acquired, further developed, and is manufactured by Sandoz AG, now Novartis AG, at its Basel, Switzerland, facility (CBER/FDA est. no. 1244). Novartis was formed by the merger of Ciba-Geigy AG and Sandoz. Simulect is marketed in the U.S. by Novartis Pharmaceutical Corp. and internationally by Novartis affiliates.

Royalty Pharma, AG for $3.25 million purchased from Ligand Pharmaceuticals its portion of royalties from sales of Simulect.

In Feb. 2006, Novartis granted Cerimon Pharmaceuticals Inc. an exclusive worldwide license to develop and market Simulect basiliximab to treat inflammatory bowel disease. The companies will share revenues from IBD sales, and Cerimon is eligible for milestone payments.

Manufacture: Bioprocessing is reported to be performed in 250 L bioreactors operating in perfusin mode using rotational sieve filters [Farid, S., Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production, presented at ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013].

FDA class: Biologic BLA

CBER class: Biological Response Modifiers

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

Approvals: Date = 19980512; first approval; BLA ref. no. 97-1251 ; orphan designation (expires 5/2005)

Date = 20030102; BLA supplement: indications: = new dosage (single dose 10 mg)

Date = 20030123; BLA supplement; Indications: = use in renal (kidney) transplantation in combination with triple immunosuppressive therapy; use in pediatric renal transplantation; and use of an IV bolus injection

Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling, 7/2004]:

Simulect is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. The efficacy of Simulect for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

Status: The BLA 97-7251 was filed on Nov. 12,1997, was granted priority review, and was approved on May 12, 1998 with orphan status; approval time = 6 months (.50 year). The filing included a 93 volume paper BLA and electronic (eBLA) submission.

A European Union application was filed on Oct. 7, 1997 and granted on Oct. 9, 1998 for prevention of acute rejection in kidney transplant recipients. Simulect received its first approval in Switzerland in April 1998.

Tech. transfer: Sandoz/Novartis nonexclusively licensed from Seragen Inc., later becam Ligand Pharmaceuticals, the “Strom” patents covering the use of IL-2 receptor antibodies for treatment of rejection and autoimmune diseases. Seragen had originally exclusively licensed the Strom patents from Beth Israel Deaconess Medical Center (Boston, MA), which received a share of royalties from Seragen and milestone payments from its sublicensees. Seragen was to receive royalties on sales starting in Jan. 2001. However, in late 1999, Ligand sold its rights to royalties from Novartis’ sales of Simulect (and also Roche’s sales of Zenapax) starting Jan. 2001 to Pharmaceutical Partners LLC (PPL; now Royalty Pharma, AG) for $3.25 million plus up to an additional $3.25 million depending on sales in 2001-2004.

Relevant patents assigned to Novartis and University College London include 6,383,487, "Methods of treatment using CD25 binding molecules," expiring May 7, 2019.

Manufacture of basiliximab also apparently involves use of recombinant antibody construction and expression patents (Cabilly patents; 4,816,567 and 6,113,415) from Genentech, Inc. See the Tech. transfer (rDNA) section of Monoclonal Antibodies entry (#300) for further information about the complex patent, licensing, cross-licensing and patent disputes concerning recombinant chimeric/humanized monoclonal antibodies.

Preparation of basiliximab is also described in EP 449769, assigned to Sandoz AG, now Novartis AG.

In Jan. 2006, Genentech and Amgen cross-licensed their respective enabling recombinant monoclonal antibody techologies.

Trials: In April 2007, Cerimon Pharmaceuticals initiated a Phase IIb clinical study, titled ARREST UC-1 (Achieve Remission & Reduce or Eliminate Steroid Therapy in Ulcerative Colitis), for the treatment of ulcerative colitis, a common type of irritable bowel syndrome (IBS).

In March 2008, Cerimon entered into an agreement with Novartis to conduct a proof of concept study for Simulect for the treatment of noninfectious uveitis, an autoimmune inflammation of the eye's internal structures that can cause severe visual impairment and accounts for an estimated 10% of blindness cases in the Western World..

Medical: Basiliximab specifically blocks the IL-2 receptor, inhibiting IL-2-driven proliferation of activated T-cells, and reducing/minimizing acute tissue rejection. Simulect is used in combination with cyclosporine and steroids for induction therapy in renal transplant patients. Sandoz Ltd., now Novartis AG, originally developed cyclosporine (which is now also available in generic formulations), and is the world’s leader in marketing rejection-related therapeutics. Neoral (cyclosporine for microemulsion) from Novartis is the worldwide leading product for the prevention of organ rejection in kidney, liver and heart transplants.

A course of treatment with Simulect generally involves a 20 mg per dose on day zero and day four following a renal transplant.

Market: The 2007 Average Wholesale Price (AWP) is $1,467.74/10 mg vial; and $1,926.43/20 mg vial (Red Book, 2007). At this later rate, a full two-dose (20 mg each) course of therapy to prevent acute rejection in renal transplant patients costs about $3,853.

Novartis does not report sales of Simulect. The author’s rough guess for 2010 worldwide sales, with no substantive information to base this on, is $50-100 million.

In Jan. 2004, the U.K. National Institute for Clinical Excellence (NICE), which provides guidelines for purchase and use of pharmaceuticals by the National Health Service (NHS), issued a final appraisal of Simulect (and Zenapax), recommending use for induction therapy in the prophylaxis of acute organ rejection in patients undergoing renal transplantation (and recommended that the cheapest recommended product be used).