C5

C5a

CD59

+

C5bC3 C3b

Factor B+D

Alternative pathway

C3bBb C3bBb3bC5b–8

C9

C6, C7, C8

C5b–9

Membraneattackcomplex

Eculizumab

FRESH FROM THE PIPELINE

EculizumabCharles J. Parker, Santwana Kar and Peter Kirkpatrick Eculizumab

Figure 1 | The complement cascade and eculizumab. Various triggers activate the

complement cascade (a selected part of which is shown for simplicity), which converges at

complement protein C5 REFS 3,4. Cleavage of C5 produces the inflammatory mediator C5a and

C5b, which then binds to C6, C7 and C8 REFS 3,4. C5b–8 forms the scaffold for C9 molecules,

which bind to form the membrane attack complex that leads to cell lysis3,4. The glycosylphos-

phatidylinositol-linked protein CD59, which is deficient on the red-blood cells of patients with

paroxysmal nocturnal haemoglobinuria (PNH), prevents the incorporation of C9 on to C5b–8,

thereby blocking the formation of the membrane attack complex3,4. Inhibition of the cleavage of

C5 by the monoclonal anti-C5 antibody eculizumab prevents the formation of the membrane

attack complex and thereby reduces the haemolysis that characterizes PNH5,6.

Eculizumab (Soliris; Alexion),

a monoclonal antibody that binds to

the terminal complement protein C5,

was approved by the FDA for the

treatment of patients with paroxysmal

nocturnal haemoglobinuria in March

2007. It is the first therapy to be

approved specifically for the treatment

of this rare blood disorder.

Paroxysmal nocturnal haemoglobinuria (PNH) is a form of haemolytic anaemia that is characterized by the production of blood cells that are deficient in the complement regulatory proteins CD55 and CD59, which makes the cells sensitive to complement-mediated destruction1. Owing to the loss of these cells, patients with PNH have symptoms such as chronic fatigue and shortness of breath1. Patients with PNH are also at risk of potentially life-threatening thrombosis, and ~50% die from the disease1.

The main approach for the treatment of PNH is supportive care with blood transfusions as required (many patients with the disease are transfusion-dependent) and treatments for the complications, such as anticoagulants2. Allogeneic stem-cell transplant can be curative, but owing to the risks, including death, it is typically limited to younger patients with a matching blood donor2. So, there is a significant need for novel treatment approaches for PNH.

Basis of discovery

PNH results from the clonal expansion of haematopoietic stem cells that have somatic mutations in the phosphatidylinositol glycan complementation class A (PIGA) gene1. This mutation blocks the synthesis of the glycolipid glycosylphosphatidylinositol (GPI), which anchors many proteins to the cell surface. Consequently, blood cells in patients with PNH have a partial deficiency (type II) or a complete deficiency (type III) in proteins that are linked to GPI1. The intravascular haemolysis that is the key feature of PNH is due to the lack of GPI-linked proteins, in particular CD55 and CD59, that protect cells from attack by the alternative pathway of complement1 — the main effector of the innate immune system.

Complement activation is a complex cascade that culminates in the production of the membrane attack complex that results in cell lysis3 (FIG. 1). The various pathways that initiate this cascade converge at the terminal complement protein C5. Cleavage of C5 produces both the potent inflammatory mediator C5a and C5b, which initiates the formation of the membrane attack complex3.

Although an inherited deficiency of any of the complement molecules upstream of C5 in the cascade results in vulnerability to pyogenic organisms and autoimmune disorders, deficiency of any of the molecules downstream of C5 has few clinical

consequences3. The only apparent result seems to be an increased risk of bacterial infection by Neisseria species3. Consequently, C5 was considered to be a good therapeutic target for PNH because blockade at this point would prevent the creation of the membrane attack complex and the release of C5a3,4.

Drug properties

Eculizumab is a humanized monoclonal antibody that binds specifically to complement protein C5 with high affinity, preventing its cleavage into C5a and C5b5,6 (FIG. 1). It thereby inhibits complement-mediated intravascular haemolysis in patients with PNH6,7.

Clinical data

The efficacy and safety of eculizumab were evaluated in a 26-week randomized double-blind placebo-controlled trial involving 87 patients with PNH6,8. Patients received meningococcal vaccination before receiving eculizumab, as the drug increases the risk of serious meningococcal infections6. The dose of eculizumab (administered as an intravenous infusion) was 600 mg every 7±2 days for 4 weeks, followed by 900 mg 7±2 days later, then 900 mg every 14±2 days for the duration of the study.

Patients receiving eculizumab had significantly reduced haemolysis, resulting in improvements in anaemia, as indicated by an increase in haemoglobin stabilization (49% of the patients in the eculizumab group had stabilized haemoglobin levels compared with 0% in the placebo group). Patients also had a reduced need for red-blood-cell transfusions (a median of 0 units of packed red cells were administered in the eculizumab group compared with 10 units in the placebo group6,8).

A second single-arm trial involving 97 patients with PNH studied eculizumab (with the same dosing regime) for 52 weeks6. A reduction in intravascular haemolysis, as measured by serum levels of lactate dehydrogenase, was sustained for the treatment period, and resulted in a reduced need for red-blood-cell transfusion and less fatigue6.

Indications

Eculizumab is approved by the FDA for the treatment of patients with PNH to reduce haemolysis6. ▶

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ANALYSIS | PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA

▶

Box 1 | Market for therapies for paroxysmal nocturnal haemoglobinuria

Analysing the market for therapies for paroxysmal nocturnal haemoglobinuria (PNH) is Santwana Kar, Business Analyst, IMS Health, London, UK.

PNH is estimated to affect ~8,000–10,000 people in North America and Western Europe. The mean age of disease onset is between 30–40 years of age and ~10% of patients newly diagnosed with PNH are 21 years of age or younger2. Nearly 50% of patients with PNH die of the disease and the median survival after diagnosis is 10 years1. Current treatment options to help ease the symptoms of PNH include transfusions, steroid and androgen hormones and anticoagulant therapy. So far, stem-cell transplantation is the only known cure. However, this is a risky procedure and the best results are achieved in younger patients with a matching sibling blood donor.

Eculizumab (Soliris; Alexion), the first agent approved specifically for this blood disorder, was launched in the US for the treatment of PNH to reduce haemolysis in March 2007. Eculizumab was recommended for approval for the treatment of patients with PNH with a history of transfusions in the EU in April 2007, with marketing authorization anticipated by July 2007. A new drug application is also expected to be filed in Japan in 2008.

At least a third of PNH patients are potential candidates for treatment with eculizumab, and strong Phase III data supports broad use, premium pricing (average treatment per year priced at US$389,000 per patient) and reimbursement as an orphan drug, which should increase the market potential for eculizumab. Evaluation of eculizumab has been completed in two Phase II studies for rheumatoid arthritis, and it is undergoing a Phase II study in membranous nephritis, as well as earlier clinical studies in dermatomyositis, psoriasis and lupus. Analysts estimate that eculizumab could have global sales of $35 million in 2007, rising to over $250 million by 2010, with sales peaking at over $500 million.

Analysing issues in the treatment of PNH is Charles J. Parker, M.D., Professor of Medicine at the Department of Hematology and Bone Marrow Transplant, University of Utah School of Medicine, Salt Lake City, Utah, USA.

Understanding the pathophysiology of PNH is critical for developing a rational management strategy9. PNH is a clonal disease of haematopoiesis, but it is not a malignant disease. In malignant clonal haematopoietic diseases such as acute leukaemia, the goal of therapy is to eradicate the mutant clone, because, untreated, the malignant clone will continue to expand uncontrollably, progressively replacing all normal haematopoiesis and eventually invading non-haematopoietic tissues. In the case of PNH, the PIGA mutant clone expands and often dominates haematopoiesis, but clonal expansion is limited to the haematopoietic compartment (that is, the bone marrow), and the clone does not behave autonomously (for example, it responds to signals that normally regulate haematopoiesis). So, the mutant clone in PNH has the characteristics of a benign rather than a malignant tumour.

PNH often arises in patients with bone-marrow injury. Hypothetically, in this setting, selection and expansion of the mutant clone results from the deficiency of one or more GPI-anchored proteins (that is the consequence of mutant PIGA), which bestows

a growth or survival advantage9. Ironically, in PNH it is the mutant clone that rescues the patient from bone-marrow failure, and, as the mutant clone is often the primary source of haematopoiesis, eradicating the clone without a mechanism for replacing it with a source of normal haematopoiesis might be detrimental. The complement-mediated intravascular haemolysis that is the primary clinical manifestation of PNH is probably an epiphenomenon owing to the fact that the complement regulatory proteins, CD55 and CD59, are GPI-anchored. So, if haemolysis is controlled, the patient will benefit from the haematopoiesis that is derived from the mutant clone without suffering the untoward consequences of deficiency of the complement regulatory proteins. By blocking complement activation, treatment with eculizumab will allow us to observe the natural history of PNH without complication by intravascular haemolysis. If the clonal haematopoiesis of PNH is truly benign, therapy that ameliorates symptoms without affecting clonal haematopoiesis should be associated with no long-term adverse consequences.

Although eculizumab is highly effective in controlling the intravascular haemolysis of PNH, some extravascular haemolysis persists because of the opsonization of erythrocytes by the activation of products of complement C3 REF. 10. Anaemia may also persist despite the use of eculizumab if the

underlying bone-marrow failure process is severe enough to limit haematopoiesis2.

Thromboembolic complications are the leading cause of morbidity and mortality in PNH. Studies that used a suboptimal experimental design suggest that by blocking intravascular haemolysis, eculizumab might also ameliorate the thrombophilia of PNH11. Although these studies suggest a role for eculizumab in the management of thromboembolic complications of PNH, this issue would be best addressed by a dedicated prospective, randomized study.

Bone-marrow transplantation is currently the only curative option for PNH, but an appropriate donor might not be available, and the procedure is associated with significant short- and long-term morbidity and mortality2. Unless our view of PNH as a benign clonal process changes, controlling symptoms without suppression or eradication of clonal haematopoiesis could be the most rational approach to its management.

Charles J. Parker is at the University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.

Santwana Kar is at IMS Health, 7 Harewood Avenue, London NW1 6JB, UK.

Peter Kirkpatrick is at Nature Reviews Drug Discovery.

e-mails: charles.parker@hsc.utah.edu; skar@uk.imshealth.com; p.kirkpatrick@nature.com

doi:10.1038/nrd2369

1. Hillman, P. et al. Natural history of paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 333,1253–1258 (1995).

2. Parker, C. et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 106, 3699–3709 (2005).

3. Rosse, W. F. et al. Immune-mediated hemolytic anaemia. Hematology 48–62 (2004).

4. Matis, L. A. & Rollins, S. A. Complement specific antibodies: designing novel anti-inflammatories. Nature Med.1, 839–842 (1995).

5. Thomas, T. C. et al. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol. Immunol. 33, 1389–1401 (1996).

6. Food and Drug Administration. FDA labelling information [online], <http://www.fda.gov/cder/foi/label/2007/125166lbl.pdf> (2007).

7. Hillmen, P. et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 350, 552–559 (2004).

8. Hillmen, P. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243 (2006).

9. Parker, C. J. The pathophysiology of paroxysmal nocturnal hemoglobinuria. Exp. Hematol. 35, 523–533 (2007).

10. Hill, A. et al. Blockade of intravascular hemolysis in PNH with the terminal complement inhibitor eculizumab unmasks low-level hemolysis potentially occurring through C3 opsonization. Blood 108, 290a (2006).

11. Hillmen, P. et al. The terminal complement inhibitor eculizumab reduces thrombosis in patients with paroxysmal nocturnal hemoglobinuria. Blood 108, 40a (2006).

Competing interests statementThe authors declare no competing financial interests.

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