IngentaConnect Eculizumab: 5G1.1, h5G1.1, Long-Acting Anti-C5 Monoclonal Antibod...

Abstract:

Eculizumab [long-acting anti-C5 monoclonal antibody 5G1-1, 5G1.1, h5G1.1, monoclonal antibody 5G1.1, Soliris™] is a monoclonal antibody that binds to the C5 complement molecule, thereby blocking the progression of the complement cascade at this point. By binding to C5, eculizumab prevents generation of the potent anaphylatoxin C5a and the cytolytic C5b-9 complex, or membrane attack complex. The compound has been filed for approval in the US and the EU for paroxysmal nocturnal haemoglobinuria (PNH), a chronic blood disease caused by a defective enzyme that leads to a lack of protective natural complement inhibitors. It is also being investigated for the treatment of asthma and transplantation.

Eculizumab is a long-acting, humanised version of the anti-C5 antibody [h5G1.1]. The short-acting version is called pexelizumab.

In January 2003 Alexion Pharmaceuticals executed a large-scale product supply agreement with Lonza Biologics for the long-term commercial manufacture of eculizumab. Specific terms of the agreement were not disclosed.

Alexion signed an agreement with GTC Biotherapeutics in 2000 for the production of eculizumab in transgenic goats. However, this agreement no longer appears to be active.

Alexion has also filed for approval for eculizumab in PNH in the EU under the centralised procedure. The EMEA has granted Alexion's request for evaluation of the proposed MAA for eculizumab in PNH under the accelerated assessment procedure. This shortens the review part of the MAA procedure.

Results from the phase III TRIUMPH trial have been reported; all pre-specified primary and secondary endpoints were achieved with statistical significance.

The last patient completed the last visit in the SHEPARD trial in October 2006, and 12-month data is being submitted to regulatory applications. Positive preliminary interim results of 6 months of therapy have been reported. The study has been conducted to collect additional data on eculizumab's safety among haemolytic PNH patients who have undergone transfusion. The trial enrolled 97 patients in the US, Canada, Europe and Australia and includes 12 months of treatment.

A pilot, open-label phase Ib trial evaluating eculizumab in 11 patients with PNH has been completed in the UK. All 11 patients in the trial chose to participate in two consecutive 1-year extension studies. One of these is still ongoing, with patients having completed at least 26 months of chronic eculizumab therapy. One- and two-year cumulative results have been presented. The positive findings further supported progression of the clinical development of eculizumab for PNH.

Eculizumab has been granted orphan drug status in the US and EU for the treatment of PNH. .

Phase I and II trials in rheumatoid arthritis had previously been completed.

The rationale behind evaluating eculizumab in this indication was that activated terminal complement proteins appear to have a central role in the pathogenesis of immune-mediated joint inflammation, indicating that anti-C5 monoclonal antibodies may have therapeutic potential for the treatment of rheumatoid arthritis.

A phase I pilot trial was completed in patients with dermatomyositis, an inflammatory skin and muscle disorder, for which eculizumab has orphan drug status in the US.

The US FDA granted eculizumab fast-track designation in membranous glomerulonephritis in early 2000 and the drug has orphan drug status in the US for idiopathic membranous glomerular nephropathy.

Both long-acting and short-acting versions of anti-C5 monoclonal antibody 5G1.1 are being developed by Alexion Pharmaceuticals in the US, with the use of technology licensed from Stanford University. Eculizumab is covered by US Patent No. 6 355 245, which extends to C5-specific monoclonal antibodies for the treatment of inflammatory diseases.

The Japanese Patent Office issued patent number 3 734 266 for eculizumab in Japan in February 2006. The patent includes the use of eculizumab to inhibit complement activation in humans, the key mechanism of action used for the treatment of PNH. Corresponding patents have been issued or are pending in Europe, Canada, Australia and other key markets.

Eculizumab: 5G1.1, h5G1.1, Long-Acting Anti-C5 Monoclonal Antibody 5G1-1, Long-Acting Anti-C5 Monoclonal Antibody 5G1.1