Alexion Receives Approval for Important Updates to the European Label for Soliris® (eculizumab)

Updated EU Label Supports Soliris Treatment of Patients with PNH Regardless of History of Transfusion

Updated EU Label Includes New aHUS Data on Efficacy of Long-term Soliris Treatment and Risks Associated with Discontinuing Treatment

LAUSANNE, Switzerland--(BUSINESS WIRE)--Alexion announced today that the European Commission (EC) has approved updates to the EU label for the therapeutic indication of Soliris^® (eculizumab) in the treatment of paroxysmal nocturnal haemoglobinuria (PNH) to now include patients without a history of transfusion. With this approval, the revised Summary of Product Characteristics (SmPC) now indicates that evidence of clinical benefit is demonstrated in patients with high disease activity as defined by elevated haemolysis (LDH ≥1.5x ULN) and the presence of related clinical symptom(s), such as fatigue, haemoglobinuria, abdominal pain, shortness of breath, anaemia, major adverse vascular event (including thrombosis), dysphagia or erectile dysfunction.¹ This update further reinforces that transfusions do not impact the underlying disease process in PNH and that haemolysis plays the central role in disease activity.

Additionally, the atypical haemolytic uraemic syndrome (aHUS) section of the EU label has been updated to include new efficacy data that specify that longer-term treatment with Soliris was associated with a greater proportion of patients achieving clinically significant benefits, as well as new information on the risks associated with treatment discontinuation. When the European Medicines Agency (EMA) approved Soliris for the treatment of patients with aHUS in 2011, the Clinical Particulars section of the SmPC (section 4) stated that Soliris treatment is “recommended to continue for the patient's lifetime, unless the discontinuation of Soliris is clinically indicated," as described in the Special warnings and precautions for use subsection. The updated label (section 4.4) has been revised to add more information on the risks of treatment discontinuation, including that “TMA complications have been observed as early as 4 weeks and up to 127 weeks following discontinuation of Soliris treatment in some patients. Discontinuation of treatment should only be considered if medically justified.” The revised label also states that “monitoring may be insufficient to predict or prevent severe thrombotic microangiopathy (TMA) complications in patients who discontinued Soliris treatment.”¹

“These label updates include important information to help optimize care for patients with PNH and aHUS, two very rare and life-threatening disorders, for which Soliris is the only approved treatment,” said Carsten Thiel, Ph.D., SVP, EMEA and Asia-Pacific, Alexion. “For patients with PNH, the updated label confirms that patients who are at high risk of morbidities or premature mortality can benefit from Soliris treatment, regardless of history of transfusion.”

Camille L. Bedrosian, M.D., Chief Medical Officer of Alexion, further stated, “For patients with aHUS, the updated label reinforces the importance of sustained therapy and specifies that a greater proportion of aHUS patients achieved clinically significant benefits with longer-term treatment.”

About the PNH Label Update

PNH is a debilitating ultra-rare blood disorder with life-threatening consequences.^2-4 In patients with PNH, chronic, uncontrolled activation of complement, a component of the normal immune system, results in haemolysis (destruction of the patient's red blood cells), leading to thrombosis, organ failure and shortened survival.^5-8

With the revised EU label, patients with PNH without a history of transfusions will now be able to benefit from treatment with Soliris. The updated label also highlights that high disease activity in PNH is defined by elevated haemolysis (LDH ≥1.5x ULN) and the presence of related clinical symptom(s): “fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin <100 g/L), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction.”¹

The EC approval is based on efficacy and safety data from an observational, non-interventional international PNH Registry, which confirmed that patients with no history of transfusion who were treated with Soliris had a significant reduction in haemolysis (measured by LDH) and clinical symptoms associated with high disease activity in PNH.

About the aHUS Label Update

aHUS is a genetic, ultra-rare, and life-threatening disease in which chronic uncontrolled complement activation results in complement-mediated TMA, the formation of blood clots in small blood vessels throughout the body.^9,10 Permanent, uncontrolled complement activation in aHUS causes a life-long risk for TMA, which leads to sudden, catastrophic, and life-threatening damage to the kidney, brain, heart, and other vital organs, and premature death.^9,11

Following the EC approval, the aHUS section of the EU label has now been revised to include new efficacy data that specify that longer-term treatment with Soliris was associated with an increased percentage of patients who experienced clinically meaningful improvements. Importantly, when Soliris treatment was continued for up to two years, more patients achieved complete TMA response and haematologic normalization. In addition, Section 4.4 of the EU label includes new information on the risks associated with treatment discontinuation in patients with aHUS.¹

This EU label update is based on additional data from long-term follow-up aHUS clinical studies, which showed that of 61 patients who discontinued Soliris treatment and were followed for a median period of 24 weeks, 15 severe TMA complications were observed in 12 patients following treatment discontinuation, and two severe TMA complications occurred in two additional patients who received a reduced dosing regimen of Soliris outside of the approved dosing regimen. Additionally serious medical complications occurred in these patients, including severe worsening of kidney function, disease-related hospitalisation and progression to end-stage renal disease requiring dialysis. These severe TMA complications occurred in patients regardless of whether they had an identified genetic mutation.

Soliris is approved in nearly 50 countries as a treatment for patients with PNH and in nearly 40 countries as a treatment for patients with aHUS.

About PNH

PNH is an ultra-rare blood disorder in which chronic, uncontrolled activation of complement, a component of the normal immune system, results in haemolysis (destruction of the patient's red blood cells). PNH strikes people of all ages, with an average age of onset in the early 30s.¹² Approximately 10% of all patients first develop symptoms at 21 years of age or younger.¹³ PNH develops without warning and can occur in men and women of all races, backgrounds and ages. PNH often goes unrecognized, with delays in diagnosis ranging from one to more than 10 years.¹⁴ In the period of time before Soliris was available, it had been estimated that approximately one-third of patients with PNH did not survive more than five years from the time of diagnosis.¹² PNH has been identified more commonly among patients with disorders of the bone marrow, including aplastic anemia (AA) and myelodysplastic syndromes (MDS).^15-17 In patients with thrombosis of unknown origin, PNH may be an underlying cause.¹²

About aHUS

aHUS is a chronic, ultra-rare, and life-threatening disease in which a life-long and permanent genetic deficiency in one or more complement regulatory genes causes chronic, uncontrolled complement activation, resulting in complement-mediated thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body.^9,10 Seventy-nine percent of all patients with aHUS die, require kidney dialysis or have permanent kidney damage within three years after diagnosis despite plasma exchange or plasma infusion (PE/PI).¹⁸ Moreover, 33 to 40 percent of patients die or progress to end-stage renal disease with the first clinical manifestation of aHUS despite PE/PI.^18,19 The majority of patients with aHUS who receive a kidney transplant commonly experience subsequent systemic TMA, resulting in a 90 percent transplant failure rate in these TMA patients.²⁰

aHUS affects both children and adults. While mutations have been identified in at least ten different complement regulatory genes, mutations are not identified in 30-50 percent of patients with a confirmed diagnosis of aHUS.¹⁸

About Soliris

Soliris is a first-in-class terminal complement inhibitor developed from the laboratory through regulatory approval and commercialization by Alexion. Soliris is approved in the US (2007), European Union (2007), Japan (2010) and other countries as the first and only treatment for patients with paroxysmal nocturnal haemoglobinuria (PNH), a debilitating, ultra-rare and life-threatening blood disorder, characterized by complement-mediated hemolysis (destruction of red blood cells). Soliris is indicated to reduce hemolysis.

Soliris is also approved in the US (2011), the European Union (2011), Japan (2013) and other countries as the first and only treatment for patients with atypical Haemolytic Uraemic Syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy, a debilitating, ultra-rare and life-threatening genetic disorder characterized by complement-mediated TMA (blood clots in small vessels). For the breakthrough medical innovation in complement inhibition, Alexion and Soliris have received the pharmaceutical industry's highest honors: the 2008 Prix Galien USA Award for Best Biotechnology Product with broad implications for future biomedical research and the 2009 Prix Galien France Award in the category of Drugs for Rare Diseases.

More information including the full prescribing information on Soliris is available at: http://ec.europa.eu/health/documents/community-register/2015/20150330131432/anx_131432_en.pdf

Important Safety Information

In Europe, the Summary of Product Characteristics (SmPC) for Soliris includes a special warning and precaution for use: Due to its mechanism of action, the use of Soliris increases the patient’s susceptibility to meningococcal infection (Neisseria meningitidis). These patients might be at risk of disease by uncommon serogroups (particularly Y, W135 and X), although meningococcal disease due to any serogroup may occur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior to receiving Soliris. aHUS patients who are treated with Soliris less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Patients must be re-vaccinated according to current medical guidelines for vaccination use. Tetravalent vaccines against serotypes A, C, Y and W135 are strongly recommended, preferably conjugated ones. Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

The most common or serious adverse reactions are headache (occurred mostly in the initial phase), leukopenia and meningococcal infection. The most common (>10%) adverse reactions reported in paediatric aHUS patients were diarrhoea, vomiting, pyrexia, upper respiratory tract infection and headache. Soliris treatment should not alter anticoagulant management. Please see Summary of Product Characteristics for full prescribing information for Soliris, including all special warnings and precautions.

About Alexion

Alexion is a biopharmaceutical company focused on serving patients with severe and rare disorders through the innovation, development and commercialization of life-transforming therapeutic products. Alexion is the global leader in complement inhibition and has developed and markets Soliris^® (eculizumab), a treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), two debilitating, ultra-rare and life-threatening disorders caused by chronic uncontrolled complement activation. The treatment is currently approved in nearly 50 countries for the treatment of PNH and in nearly 40 countries for the treatment of aHUS. Alexion is evaluating other potential indications for Soliris in additional severe and ultra-rare disorders beyond PNH and aHUS, and is developing other highly innovative biotechnology product candidates, including asfotase alfa, across multiple therapeutic areas.

Further information about Alexion can be found at: www.alexionpharma.eu.

References
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