Status: marketed in U.S and EU

Organizations involved:

Alexion Pharmaceuticals, Inc. – Manuf.; R&D; Tech.; World mark.

Lonza Biologics plc – Manuf.

Yale University – R&D; Tech.

PDL BioPharma Inc. – Patent dispute

Novartis AG - Patent dispute

Oklahoma Medical Research Foundation (OMRF) – Patent dispute; Tech

Cross ref.: See the Monoclonal Antibodies entry (#300)

Description: Soliris is an aqueous formulation of eculizumab (h5G1.1), a recombinant humanized version of the 5G1.1 murine (mouse) IgG2/4kappa monoclonal antibody, apparently expressed by transformed NS0 murine (mouse) myeloma cells (with the product insert only stating it is “produced by murine myeloma cell culture”). The monoclonal antibody was derived from portions of the 5G1.1 murine antibody expressed by the 5G1.1 hybridoma cell line (ATCC HB-11625). Eculizumab contains human constant (framework; non-immunogen-binding) regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions (CRDs; mmunogen-binding regions) grafted onto the human framework light- and heavy-chain variable regions. Eculizumab selectively binds to the C5 component of human complement, preventing its cleavage into its pro-inflammatory components. Eculizumab is an antibody-like dimer composed of two 448 amino acid heavy chains and two 214 amino acid light chains, and has a molecular weight of ~148 kDa.

Soliris is packaged as a sterile, clear, colorless, preservative-free 10 mg/mL solution for intravenous infusion in 30-mL single-use vials. Each vial contains 300 mg of eculizumab, 13.8 mg sodium phosphate monobasic, 53.4 mg sodium phosphate dibasic, 263.1 mg sodium chloride, 6.6 mg polysorbate 80 (Tween 80; vegetable origin) and Water for Injection, USP -- at pH 7. Vials must be stored under conditions at 2-8°C (36-46°F; refrigerated). Each vial is stamped with an expiration date.

Nomenclature: Complement C5 Mab, rDNA [BIO]; Soliris [TR]; eculizumab [USAN]; immunoglobulin, anti-(human complement C5 alpha-chain)(human-mouse monoclonal 5G1.1 heavy chain), disulfide with human-mouse monoclonal 5G.1.1 light chain, dimer [CAS]; 219685-50-4 [CAS RN]; h5G1.1 [SY]; rh5G1.1 [SY]; h5G1.1VHC+h5G1.1VLC [SY]; complement C5 monoclonal antibody, recombinant [SY]; NDC 25682-001-01 [NDC]

Biological.: Eculizumab binds to human complement and prevents the cleavage of its C5 portion to form C5a and C5b, which have toxic effects. Eculizumab binds to an epitope within the amino acid sequence Val-Ile-Asp-His-Gln-Gly-Thr-Lys-Ser-Ser-Lys-Cys-Val-Arg-Gln-Lys-Val-Glu-Gly-Ser-Ser, referred to as the KSSKC epitope. This prevents the generation of the anaphylatoxic activity associated with the breakdown of C5a, and prevents assembly of the membrane attack complex associated with C5b.

The complement system acts in conjunction with other immunological systems of the body to defend against intrusion of cellular and viral pathogens. There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events. The resulting complement cascade leads to products with opsonic, immunoregulatory, and lytic functions.

The complement cascade progresses via the classical pathway or the alternative pathway. These pathways share many components, and while they differ in their initial steps, they converge and share the same “terminal complement” components (C5 through C9) responsible for the activation and destruction of targeted cells. The classical complement pathway is typically initiated by antibody recognition of and binding to an antigenic site on a target cell. The alternative pathway is usually antibody-independent, and can be initiated by certain molecules on pathogen surfaces. Both pathways converge at the point where complement component C3 is cleaved by an active protease (which is different in each pathway) to yield C3a and C3b. Other pathways activating complement attack can act later in the sequence of events, leading to various aspects of complement function.

C5a is cleaved from the alpha chain of C5 by either alternative or classical C5 convertase as an amino terminal fragment comprising the first 74 amino acids of the alpha chain (i.e., amino acid residues 660-733). Agents, such as eculizumab, that bind at or adjacent to this cleavage site have the potential to block access of the C5 convertase enzymes to the cleavage site and act as a complement inhibitor. Eculizumab does not impair the opsonization function associated with the activation of complement component C3 by a C3 convertase, and does not result in reduction in plasma C3a levels. In animal models eculizumab administered subsequent to the onset of glomerulonephritis essentially eliminates glomerular inflammation/enlargement and reduces kidney dysfunction.

C3a and C5a are both anaphylatoxins. These activated complement components can trigger mast cell degranulation, which releases histamine and other mediators of inflammation, resulting in smooth muscle contraction, increased vascular permeability, leukocyte activation, and other inflammatory phenomena. C5a also functions as a chemotactic peptide that serves to attract pro-inflammatory granulocytes to the site of complement activation. Direct activation of endothelial cells by C5a induces the release of the coagulation-inhibiting glycoprotein heparan sulfate. This can have the effect of decreasing the levels of this coagulation-inhibiting molecule at the endothelial cell surface, increasing the thrombogenic potential of the endothelial cell surface.

C5a is an anaphylatoxin. C5a also functions as a chemotactic peptide that serves to attract pro-inflammatory granulocytes to the site of complement activation. C5b combines with C6, C7, and C8 to form the C5b-8 complex at the surface of the target cell. Upon binding of several C9 molecules, the membrane attack complex (MAC, C5b-9, terminal complement complex—TCC) is formed. When sufficient numbers of MACs insert into target cell membranes, the openings (MAC pores) they create mediate rapid osmotic lysis of the target cells. Lower, non-lytic concentrations of MACs can produce other effects, e.g., membrane insertion of small numbers of the C5b-9 complexes into endothelial cells and platelets can cause deleterious cell activation. In some cases activation may precede cell lysis.

C3a, resulting from cleavage of complement component C3, is also an anaphylotoxin. C3b (opsonin), also resulting from C3 cleavage, binds to bacterial and other cells and tags them for removal from the circulation. (C3b in this role is known as opsonin.) C3b also forms a complex with other components unique to each pathway to form classical or alternative C5 convertase, which cleaves C5 into C5a and C5b. C3 is regarded as the central protein in the complement reaction sequence, since it is essential to both the alternative and classical pathways. The opsonic function of C3b is considered to be the most important anti-infective action of the complement system. C3 is the central protein in the complement reaction sequence, since it is essential to both the alternative and classical pathways.

The 5G1.1 native murine anti-KSSKC monoclonal antibody substantially blocks both complement hemolytic activity and the generation of C5a at a stoichiometric ratio of antibody to C5 that approaches the theoretical one to two (antibody to antigen) limit of binding that can be achieved by a bivalent antibody. This allows smaller doses of antibody to achieve therapeutic effects than would be required of otherwise similar antibodies that cannot function at such a ratio.

Eculizumab, derived from murine 5G1.1 monoclonal antibody, shares binding properties with 5G1.1, and substantially blocks both complement hemolytic activity and the generation of the proinflammatory complement cleavage product C5a. Through blocking the generation or activity of the toxic C5a and/or C5b active fragments of complement component C5, eculizumab inhibits the proinflammatory (anaphylatoxic) effects of C5a and the generation of the C5b-9 membrane attack complex (MAC). Since this occurs at the level of complement component C5, this has the advantage of maintaining opsonic, anti-infective, and immune complex clearance functions of the complement system mediated by complement component C3.

Companies.: Alexion Pharmaceuticals developed and retains worldwide manufacturing and marketing rights for eculizumab. In Jan. 2003, Alexion Pharmaceuticals concluded a contract with Lonza Biologics for commercial manufacturing of eculizumab. But FDA now recognizes Alexion, CBER/FDA est. no. 1743, as the manufacturer of Soliris.

In July 2006, Alexion purchased a former Dow Chemical Co. contract biopharmaceutical manufacturing facility in Smithfield, Rhode Island. This will be used primarily to produce Soliris. This facility is expected to “meet world-wide demand for the product.” The ~55,000 square foot facility was expected to begin operations in 2008. Alexion retrofitted the facility to include two 10,000 liter bioreactors and associated purification suites along with a pilot plant. The facility was designed to meet both FDA and EMEA/European Union good manufacturing practices. Alexion expected to continue to source supply from Lonza after the new facility is in operation.

In Dec. 2009, Alexion Pharmaceuticals’ manufacturing facility in Rhode Island received a positive opinion from the CHMP. The CHMP’s positive opinion recommended the European Commission approve the site, which was expected to occur in early 2010. Alexion expected in early 2010 to meet with FDA regarding approval of its new manufacturing facility. In June 2010, FDA has approved Alexion Pharmaceuticals’ Rhode Island plant for commercial supply of Soliris (eculizumab), giving Alexion a second source. The Rhode Island plant and Lonza can meet all forecasted commercial and clinical needs in the U.S. and Europe.

In March 2013, with Alexion's Soliris manufacturing facility issued an FDA warning letter, it was reported that Lonza also was actively manufacturing the product, with no shortages expected as Alexion resolves its problems.

Manufacture: Several different recombinant vectors for eculizumab expression are described as preferred and/or used in examples in U.S. patents. One particularly preferred eukaryotic vector is plasmid pAPEX-3p, and derivatives of the vector pcDNAI/Amp (Invitrogen) which was modified to increase protein expression levels; and pAPEX-3, a derivative of the vector pDR2 (Clontech Labs.). Purification apparently includes cation exchange chromatography using POROS HS resin (PerSeptive Biosystems) .

FDA class: Biologic BLA

Approvals: Date = 20070306; original BLA

Date = 20110923; BLA supplement; Indication = treat patients with atypical Hemolytic Uremic Syndrome (aHUS; which accounts for 5 to 10 percent of all cases of hemolytic uremic syndrome)

indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling; 7/2012];

1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH)
Soliris is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.
1.2 Atypical Hemolytic Uremic Syndrome (aHUS)
Soliris is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy.
The effectiveness of Soliris in aHUS is based on the effects on thrombotic microangiopathy (TMA) and renal function. Prospective clinical trials in additional patients are ongoing to confirm the benefit of Soliris in patients with aHUS.
Limitation of Use
Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

Status: Initial filings for approvals have been for treatment of paroxysmal nocturnal plasmid hemoglobinuria (PNH). Soliris approval was based primarily on the TRIUMPH and SHEPHERD Phase III pivotal trials for PNH. These two Phase III trials were conducted under a Special Protocol Assessment (SPA) from FDA (involving FDA review and approval of trials protocols expected to be sufficient to support approvals). Alexion plans to launch Soliris for PNH in at least 40 countries within three years of its first commercial launch (in the U.S.).

On Sept. 20, 2006, Alexion submitted its BLA to FDA seeking approval of Soliris for paroxysmal nocturnal hemoglobinuria (PNH). This was accepted for filling in Nov. 2006, FDA granted Priority Review to the BLA. On March 6, 2007 (approval time <..5 year), the BLA was approved, with FDA granting New Molecular Entity (NME) status to Soliris. With this approval, Soliris became the first therapy approved for PNH). Approval was largely based on three multi-national clinical studies: TRIUMPH, a placebo-controlled 26 week Phase III study involving 87 PNH patients; SHEPHERD, an open-label 52 week Phase III trial involving 97 PNH patients; and E05-001, a long term extension study (see the Trials section below).

Soliris has been granted orphan drug status by both the FDA and the European Union (EMEA).

In Nov. 2006, Alexion announced that its European Union MAA for the use of Soliris for PNH had been accepted. This wsa the first filing to be reviewed under the EU’s Accelerated Assessment procedure (providing a shortened review period; 150 days vs. 210 days). In April 2007, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending approval of Soliris as the first product to be evaluated by accelerated assessment. The review time was 147 days. On June 26, 2007, the EU granted accelerated approval to Soliris for treatment of PNH.

In Dec. 2006, Alexion initiated an expanded access program, EMBRACE (The Paroxysmal Nocturnal Hemoglobinuria Early Access Treatment Protocol), in the U.S. for Soliris. This continued until FDA approval was granted.

In Sept. 2011, Soliris was appoved for atypical hemolytic uremic syndrome (aHUS), an orphan indication after receiving priority review. This was the first FDA-approved treatments for aHUS; and the safety and effectiveness of current standard treatment, plasma therapy (plasma exchange or fresh frozen plasma infusion), has not been studied in well controlled trials. This new indication for Soliris was approved with an extension of the existing Risk Evaluation and Mitigation Strategy (REMS), to inform health care professionals and patients about the known risk of life-threatening meningococcal infections. Soliris continued to be available only through a restricted program, and prescribers must enroll in a registration program and provide a medication guide to patients who receive Soliris.

On Nov. 29, 2011, EMA/EU granted approval for atypical hemolytic uremic syndrome.

Tech. transfer: U.S. 6,355,245, “C5-specific antibodies for the treatment of inflammatory diseases,” March 12, 2002, assigned to Alexion, a continuation of 6,074,642, claims use of eculizumab and other monoclonal antibodies monoclonal for treatment of glomerulonephritis. Claim 1 states, “An antibody comprising at least one antibody-antigen binding site, said antibody exhibiting specific binding to human complement component C5, said specific binding being targeted to the alpha chain of human complement component C5, wherein the antibody 1) inhibits complement activation in a human body fluid, 2) inhibits the binding of purified human complement component C5 to either human complement component C3 or human complement component C4, and 3) does not specifically bind to the human complement activation product free C5a.” Further claims include blockage of C5a generation and associatated complement hemolytic activity, including 60-90% reduction in the ability of C5 to bind to human complement component C3 and C4.

U.s. 6,355,245 was extemded by 735 days, now expiring March 16, 2021

Alexion has applied for supplementary protection certificates (SPCs) in the 14 European countries where the equivalent patent issued. Together with the patent, issued SPCs (country-by-country) would include a prohibition on the sale or use by third parties of Soliris until May 1, 2020 for all approved indications, the company stated.

U.S. 5,853,722, “Use of C5-specific antibodies for reducing immune and hemostatic dysfunctions during extracorporeal circulation,” coassigned to Alexion Pharmaceuticals, Inc. and Yale University, claims use of eculizumab to reduce the dysfunction of the immune and hemostatic systems associated with extracorporeal circulation procedures, such as, cardiopulmonary bypass procedures.

U.S. 5,627,264, “Chimeric complement inhibitor proteins,” coassigned to Alexion Pharmaceuticals, Inc. and Yale University, claims eculizumab and related recombinant monoclonal antibody constructs. These chimeric complement inhibitor proteins have a functional domain (amino acid sequence) having C3 inhibitory activity and a second functional domain having C5b-9 inhibitory activity. The first functional domain is amino terminal to the second functional domain. Thus, the chimeric protein exhibits both C3 and C5b-9 inhibitory activity.

On March 16, 2007, shortly after Soliris received FDA approval, PDL BioPharma Inc. filed a suit in U.S. District Court against Alexion alleging infringment of PDL patents concerning monoclonal antibody humanization. PDL did not seek an injunction against marketing of Alexion. See the Monoclonal Antibodies entry (#300) for further information about PDL’s broad antibody humanization patents (“Queen” patents)

In Feb. 2008, Alexion acquired all rights to patents assigned to Oklahoma Medical Research Foundation (OMRF) relating to the treatment of complement system mediated disorders. Alexion had had partial rights to these patents since its founding. Alexion paid OMRF $10 million to acquire all rights and interests to the patents, in various amounts to be remitted in 2008 and the first half of 2009. No further amounts, including royalties, will be owed to OMRF. OMRF and Alexion dismissed suits and counter suits then pending in the U.S. District Court for the Northern District of Oklahoma. The patents now fully owned by Alexion include 5,135,916 and 5,550,108, both titled "Inhibition of complement mediated inflammatory response," concerning polypeptide inhibitors of complement C5b-9 complex activity; 5,635,178, " Inhibition of complement mediated inflammatory response using monoclonal antibodies specific for a component forming the C56-9 complex which inhibit the platelet or endothelial cell activating function of the C56-9 complex," concerning monoclonal antibodies and fragments as inhibitors of complement C5b-9 complex activity; 5,660,825, " Method of inhibition of complement mediated inflammatory response, concerning polypeptides that inhibit complement C5b-9 complex activity; and 5,763,156, " Inhibition of complement mediated inflammatory response," concerning polypeptides that inhibit complement C5b-9 complex activity.

In Jan. 2009, PDL BioPharma, Inc. and Alexion Pharmaceuticals, Inc. settled their patent disputes. PDL granted Alexion a license under certain claims in the Queen patent portfolio, and provided Alexion a covenant not to sue in respect of other claims in the Queen patent portfolio, thus permitting Alexion to commercialize Soliris for all indications: under the Queen patents. In consideration of this license, Alexion paid PDL $25 million. No additional payments will be owed by Alexion to PDL under the Queen patents in respect of Soliris sales for any indication. As part of the settlement, Alexion confirmed that the Queen patent claims are valid and that Soliris employs technology covered under the Queen patents. Alexion agreed not to challenge or assist other parties in challenging the validity of the Queen patents in the future. PDL separately granted Alexion the right to take a royalty-bearing license under PDL's Queen patents to commercialize additional Alexion humanized antibodies that may be covered by the Queen patents in the future. In the event that Alexion takes such a license, Alexion will pay PDL a royalty of 4% of net sales of such non-Soliris products.

In Aug. 2010, Novartis AG filed a challenge to Soliris' main European Patent. Alexion had applied for supplementary protection certificates in the 14 European countries where the patent issued. Together with the patent, set to expire in 2015, issued SPCs would include a prohibition on the sale or use by third parties of Soliris until May 1, 2020 for all approved indications:.

Trials: On Jan. 26, 2006, Alexion reported positive preliminary results from its 6-month TRIUMPH Phase III pivotal trial with Soliris for treatment of paroxysmal nocturnal hemoglobinuria (PNH). The trial met the co-primary endpoints of transfusion rate and hemoglobin stabilization with statistical significance. All secondary endpoints were also achieved with statistical significance. The companion SHEPHERD was an open-label Phase III trial in PNH patients, designed provide safety and additional efficacy data for Soliris in a wider range of PHN patients. Both of the pivotal Phase III trials, TRIUMPH and SHEPHERD, were completed in 2006.

In the Sept. 21, 2006, issue of the New England Journal of Medicine, final results were reported from the 12-month TRIUMPH trial. In this double-blind, randomized, placebo-controlled Phase III efficacy study, 87 patients were treated at 34 sites in the U.S., Canada, Europe, and Australia. Clinically significant improvements were shown in anaemia and the quality of life for patients with PNH. Patients received either placebo or eculizumab intravenously. Eculizumab significantly improved anaemia in patients as both primary endpoints were achieved, including median transfusion rate and hemoglobin stabilization over six months. The median transfusion rate was reduced from 10 units per patient with placebo to 0 units per patient with eculizumab (p<0.001). Hemoglobin stabilization was achieved by 49% of eculizumab patients vs, 0% for placebo (p<0.001). Patients treated with eculizumab also experienced significantly less intravascular hemolysis, fatigue, pain, and shortness of breath, along with improvements in overall health status and functioning.

In Dec. 2006, results were reported from the open label Phase III SHEPHERD PNH study. The pre-specified primary endpoints of the trial were safety and a reduction in intravascular hemolysis as measured by the surrogate endpoint lactate dehydrogenase (LDH). Secondary endpoints included fatigue and intravascular hemolysis. Other endpoints included patient reported outcomes and measures of anemia including transfusion requirements. Soliris was well tolerated with an adverse event profile similar to that of placebo in the Phase III TRIUMPH study. No serious adverse events were deemed probably or definitely related to treatment. The most common adverse events reported with Soliris were headache, nasopharyngitis, nausea and upper respiratory tract infection. These events were generally consistent with those observed with eculizumab during six months of treatment in TRIUMPH and with six months of placebo treatment in TRIUMPH. Soliris appeared to be safe and well tolerated, and provide clinically and statistically significant improvements in intravascular hemolysis, anemia, fatigue and quality of life in patients with PNH during the study’s 52 weeks of treatment. The CEO of Alexion noted, “Data from the open-label SHEPHERD study show that eculizumab may provide significant clinical benefit to a broader, more diverse population of PNH patients than previously observed in TRIUMPH.”

In June 2007, Alexion reported results from a trial indicating that Soliris is effective in patients diagnosed with PNH who have a history of aplastic anemia (AA) or myelodysplastic syndromes (MDS). Alexion also announced expansion of an ongoing study to examine the frequency of PNH in patients with AA, MDS and other bone marrow disorders. Alexion now plans to enroll up to 10,000 patients in the EXPLORE trial (EXamination of PNH, by Level Of CD59 on Red and white blood cells, in bone marrow failure syndromes). Since beginning the EXPLORE trial in June 2006 with an initial target of 2,000 patients, Alexion has enrolled 1,500 patients.

In Aug. 2007, a study to be published in Blood showed that among 95 patients in Soliris' Phase II and Phase III trials, including TRIUMPH and SHEPHERD, there was a 92% reduction in incidence of life-threatening blood clots (thromboses) after treatment with Soliris (p<0.0001). Approximately 40% of patients with PNH experience thrombosis during the course of the disease. An initial thrombosis increases the relative risk of death by five- to ten-fold for PNH patients. Patients were treated with Soliris for up to 54 months. Soliris reduced hemolysis in all treated patients and reduced thrombosis by 92%, with three events during Soliris treatment compared to 39 events during the same period of time prior to treatment (P<0.0001). The collection of thrombotic events was defined prospectively by clinical trial protocols.

In March 2010, Biogen Idec and Elan begam enrollment in a global Phase IIIb, randomized, rater-blinded, active-controlled study designed to evaluate switching to Tysabri from Copaxone(R) (glatiramer acetate) or Rebif (interferon beta-1a) in patients with relapsing remitting multiple sclerosis (RRMS). The study, called SURPASS, is expected to enroll 1,800 patients in 27 countries and provide direct, head-to-head comparative data of different treatment options for RRMS patients who experience breakthrough disease activity.

The sBLA for aHUA was based on two single-arm trials in 37 adults and adolescent patients with aHUS and one retrospective study in 19 pediatric patients and 11 adult patients with aHUS. Patients treated with Soliris in these studies experienced a favorable improvement in kidney function, including elimination of the requirement for dialysis in several patients with aHUS that did not respond to plasma therapy. Patients treated with Soliris also exhibited improvement in platelet counts and other blood parameters that correlate with aHUS disease activity.

Medical: The typical dosage regimen is 600 mg via 35 minute intravenous infusion every 7 days for the first 4 weeks, followed by 900 mg for the fifth dose 7 days later, then 900 mg every 14 days thereafter

Prior to beginning Soliris therapy, all patients and their physicians are enrolled in the Soliris Safety Registry, which is part of a special risk management program that involves initial and continuing education and long-term monitoring for detection of new safety findings.

The U.S. product labeling/insert for Soliris includes a boxed warning: “Soliris increases the risk of meningococcal infections. Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of Soliris; revaccinate according to current medical guidelines for vaccine use. Monitor patients for early signs of meningococcal infections....” In trials, 2 out of 196 vaccinated PNH patients treated with Soliris experienced a serious meningococcal infection.

Disease: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare genetic disease resulting from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. Note, although a genetic disease, PNH is not hereditary, i.e., passed on by one or both parents. Patients with PNH lack complement inhibitors to prevent red blood cell destruction. PNH is characterized by autoimmune destruction of erythrocytes (red blood cells) by the body’s complement system (a component of the immune system).

Patients with PNH have chronic destruction of red blood cells causing both anaemia and the release of free haemoglobin. The need for transfusion is common in order to sustain tolerable levels of hemoglobin and maintain quality of life. PNH has an average age of onset in the early 30’s. The estimated median survival for PNH patients is between 10- 15 years from the time of diagnosis. Patients with PNH often have a poor quality of life and may suffer from severe hemolysis, anemia, chronic fatigue, recurrent pain, pulmonary hypertension and intermittent episodes of dark colored urine, known as hemoglobinuria. PNH patients are at increased risk of forming life-threatening blood clots, or thromboses, which are a leading cause of death in this disease. There currently is no therapy specifically available for treatment of PNH.

It is currently estimated that approximately 8,000-10,000 people in North America and Western Europe suffer from PNH, based upon studies of the prevalence of patients diagnosed with abnormal PNH cells in their blood. However, this estimate may not be applicable to Asian populations, where reports suggest prevalence may be higher.

aHUS is a chronic, ultra-rare disease characterized by thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body, causing a reduction in platelet count and life-threatening damage to the kidney, brain, heart and other vital organs. Approximately 60% of patients with aHUS require dialysis or a kidney transplant or die within a year of diagnosis. The majority of patients with aHUS who receive a kidney transplant experience severe complications of the disease, and more than 90% of these patients experience failure of the donor kidney.

Market: Soliris for treatment of PNH presents a relatively small orphan market. However, as with various enzyme replacement products for orphan diseases for which no treatments are currently available, Soliris is priced at a premium, such that total sales in the hundreds of millions of dollars are attainable. With no other treatment available for PNH, the market (including reimbursement/insurance plans) accepts a premium price for Soliris.

Soliiris is the most expensive therapeutic. In Dec. 2012 and Feb. 2013, Alexion reported it cost about $409,500/year. Soliris treatment at launch was reported to cost more than $389,000/year (in the U.S.). Illustrating the value of Soliris, PNH patients followed for up to eight years on treatment can expect the same life span as those of a normal population that are age- and gender-matched, while If left untreated, PNH has a 35% mortality rate at five years.

Total 2012 sales were 1.134 billion; about $783 million in 2011, $541 million in 2010, and 2009 were $387 million, up from about $270 in 2008 and $66.4 million in 2007. About 90% or more of sales have been in the U.S. and Europe.

In June 2013, Alexion Pharmaceuticals reported it wasa planning on expanding the Soliris franchise with the following 5 additional indications : STEC-HUS; Neuromyelitis Optica (NMO); MG Kidney transplant; Delayed transplant graft function; and Myasthenia Gravis.

Upon U.S. approval, Alexion launched OneSource, a treatment support service for all PNH patients and their healthcare providers. Each patient enrolled in the program receives support from an Alexion Case Manager at OneSource who provides education about PNH and Soliris and facilitates solutions to help patients obtain Soliris. Alexion’s goal is that all PNH patients who can benefit from Soliris will have access to it.

Many analysts had originally projected that Soliris will attain peak sales of about $500 million/year.

In Jan. 2013, Alexion reported Soliris was on track to attain over $1 billion/year (blockbuster) sales, and that 2/3rds of sales were outside the U.S. Also, Soliris had secured public funding (government insurance coverage) in such jurisdictions as Australia and Canada—two countries well known for being perhaps even more restrictive than the EU.

In June 2010, Mehta Partners forecast sales increasing to $1 billion in 2014.