Soliris (eculizumab) is a drug indicated for the treatment of paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome (aHUS), generalised myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD).

The drug is developed and manufactured by Alexion Pharmaceuticals. Soliris was given orphan drug designation by the US FDA in October 2003. Alexion submitted its new drug application (NDA) for Soliris to the FDA in September 2006.

The FDA first approved the drug in 2007 for the treatment of PNH in patients. Soliris also received FDA approval for the treatment of aHUS, gMG, and NMOSD.

Soliris was approved by the Australian Therapeutic Goods Administration for the treatment of PNH in February 2009.

The drug is also approved in the EU, Canada and Japan for the treatment of PNH, aHUS and gMG.

Causes of PNH, aHUS, gMG and NMOSD

PNH and aHUS are caused due to defects in protein (CD59) present on the surface of RBCs. This protein hinders complement protein from attacking the cells, thereby leading to the destruction of RBCs.

PNH is the breakdown of the red blood cells (RBC) at an early stage. It usually occurs in people with the missing PIG-A gene, which helps proteins to stick to the RBC. In the absence of PIG-A, the proteins cannot stick to the cells, which results in the breakdown of the RBC.

AHUS is a chronic illness in which a genetic deficiency may lead to uncontrolled activation of complement protein that further leads to the formation of small clots in blood vessels all over the body.

The uncontrolled complement activation may lead to reduced platelet count (thrombocytopenia) and destruction of RBC. It may also cause damage to many vital organs, including the kidneys, brain and heart.

gMG is a chronic autoimmune neuromuscular disease, which starts with muscle weakness around eyeballs and eyelids and leads to weakness in head, neck, limb and respiratory muscles. It occurs due to the generation of antibodies by the patient’s own body to attack the AChR receptor present on the muscle cells of the neuromuscular junction.

NMOSD is a rare, debilitating disorder in which the patient’s own body generates auto-antibodies against AQP4 protein. The protein is present in the nerve cells of eyes, brain and spinal cord for its growth and survival, and the AQP4 auto-antibodies destroy the essential cells in the CNS and neurons.

Soliris mechanism of action

Eculizumab, the active ingredient of Soliris, is a recombinant monoclonal antibody that recognises and adheres to antigens present in the human body.

Eculizumab adheres to the C5 complement protein and blocks it. The C5 complement protein is a part of the immune system’s complement cascade whose activation is responsible for the development of the above conditions.

Clinical trials in PNH patients

TRIUMPH, a Phase III trial, was initiated in November 2004 to evaluate and compare the safety and efficacy of Soliris to that of a placebo. It recruited 87 patients at 45 sites in the US, Canada, Europe and Australia.

The trial data released in September 2006 showed reductions in the symptoms of PNH. Hematologic normalisation was observed in 47% of Soliris-treated patients when compared to 0% subject to a placebo.

Phase III SHEPHARD (safety in hemolytic PNH patients treated with eculizumab) trial enrolled 87 patients. It was initiated in August 2005 to evaluate the safety and efficacy of the drug in PNH patients. It was completed by June 2007.

Phase III AEGIS trial was conducted to evaluate the efficacy of Soliris in 29 Japanese PNH patients in 2008. An 86% reduction in haemolysis was observed.

The AEGIS extension study was conducted for 26 weeks. A decrease in haemolysis was observed in Soliris-treated patients.

Clinical trials in aHUS patients

The FDA approval for aHUS was based on three Phase II studies conducted to evaluate the safety and efficacy of the drug in aHUS patients undergoing plasma-therapy, paediatric aHUS patients and plasma-therapy resistant patients respectively. The first Phase II study enrolled 17 plasma-therapy resistant or sensitive patients. Hematologic normalisation was observed in 76% of the patients (13 of 17). About 87% of the patients (15 of 17) treated with Soliris achieved thrombotic microangiopathy (TMA)-free status.

The second trial was conducted in aHUS patients undergoing plasma-therapy. It enrolled 20 patients and 80% of them (16 of 20) achieved TMA-free status. Hematologic normalisation was observed in 90% of the patients.

The third trial recruited 19 paediatric aHUS patients. Hematologic normalisation was observed in 89% of the patients.

The final trial data from all the three trials was presented in June 2011 to the European Haematology Association.

Clinical trials in gMG and NMOSD patients

The FDA’s approval of the drug for gMG was based on the Phase III, randomised, double-blind, placebo-controlled, multi-centre clinical study named REGAIN while the approval for NMOSD was based on the results of a Phase III, randomised, double-blind, placebo-controlled study named PREVENT.

In the REGAIN study, 125 patients were enrolled for 26 weeks. The primary endpoint of the study was the change in the total score of Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL). The total score was -4.2 in Soliris-treated patients compared to -2.3 in patients receiving a placebo. A lower score indicates a better clinical outcome.

A total of 143 patients were enrolled in the PREVENT trial, in which 96% of patients receiving Soliris were relapse-free compared to 45% patients on placebo at 144 weeks.