Soliris – Treatment for PNH and aHUS

Soliris (Eculizumab) is a drug indicated for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

The drug is developed and manufactured by Alexion Pharmaceuticals. Soliris was given orphan drug designation by the US FDA in October 2003. It is the first and only approved drug indicated for the treatment of PNH and aHUS.

Alexion submitted its New Drug Application (NDA) for Soliris to the FDA in September 2006. The FDA put the drug under priority review in May 2007 for the treatment of all PNH patients (paediatric and adult patients).

Alexion also submitted the marketing authorisation application (MAA) to the European Medicines Agency (EMA) in the same year. The drug was approved for use in the treatment of all PNH patients in Europe in June 2007.

Soliris was approved by Health Canada and Australian Therapeutic Goods Administration for the treatment of PNH in January and February 2009 respectively. It was approved by Japan’s Ministry of Health, Labour and Welfare for use in the treatment of PNH patients in April 2010.

Alexion submitted marketing application of Soliris to the FDA for the treatment of aHUS patients in April 2011. The FDA approved the drug for the corresponding indication in September 2011. The approval was based on the Phase II studies conducted in paediatric and adult aHUS patients.

MAA of the drug for the treatment of aHUS patients was submitted to the EMA in April 2011. The drug received a positive opinion in September 2011.

Causes of PNH and aHUS

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 breakdown of the red blood cells (RBC) at an early stage. It is usually caused 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 which further leads to 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.

Soliris mechanism of action

Eculizumab, the active ingredient of soliris, is a recombinant monoclonal antibody which can recognise and adhere to antigens present in the human body.

Eculizumab adheres to the C5 complement protein and hence blocks it. It stops the complement protein from attacking the RBCs and prevents the destruction of RBCs. Thus it gives relief from the disease symptoms.

Clinical trials in PNH patients

Pre-clinical studies were conducted in mice for a period of 26 months with a surrogate antibody targeting murine C5. Reduced hemolytic activity was observed in both male and female mice.

The first Phase II trial conducted in 11 PNH patients showed reduced haemolytic activity and an increase in red cell clone size.

The Phase II trial conducted to evaluate the safety and efficacy of soliris in haemolytic PNH patients enrolled 29 patients. The trial was initiated in November 2007 and completed by October 2008.

Another Phase II trial was initiated in March 2008 to evaluate the long term safety and efficacy of the drug in 27 PNH patients. The patients were administered 900mg of Soliris intravenously every 14 days. The trial was completed in March 2011 with primary completion in September 2010.

A Phase I/II trial is being conducted to evaluate the safety and efficacy of soliris in paediatric patients. The trial enrolled eight patients. It was initiated in May 2009 and is scheduled to be completed by June 2012.

Phase III 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% in case of 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. Around 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.