The evidence for the effectiveness of Soliris as a treatment for PNH

With over 10 years of clinical evidence now available, there can be no questions as to the efficacy of Soliris (eculizumab) in reducing the harmful effects of the PNH disease. 

Research based on clinical experience in the United Kingdom, published in 2011, demonstrated that the Soliris treatment returned mortality rates for PNH patients to those of the general population. The findings from this research, "Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival," are shown below. 
 
In 2012 further follow-up was conducted in the United Kingdom, with data now available from a 10 year period and outcomes for 153 patients. The findings from this report, "Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the United Kingdom 10-Year Experience," are also shown below. 

Further analysis is provided below in the report, "Eculizumab Protects Against Thromboembolism and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study". This data comes from the International PNH Registry, with 1547 PNH patients registered internationally. 

Definitions
Thromboembolism (TE): Formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. The clot may plug a vessel in the lungs (pulmonary embolism), brain (stroke), gastrointestinal tract, kidneys, or leg. Thromboembolism is a significant cause of morbidity (disease) and mortality (death).

Intravascular Hemolysis: The destruction of red blood cells within the circulation, leading to the release of haemoglobin from within the red blood cells into the blood plasma.

Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the United Kingdom 10-Year Experience. 

Conclusions
  • The UK PNH service now has more than 10 years of experience managing PNH with eculizumab.
  • The results from this UK PNH patient cohort demonstrate that the significant clinical benefits and long-term safety of eculizumab were sustained over 10 years of treatment.
Long-term eculizumab treatment led to:
  • Significant improvement in survival,
  • A significant reduction in the incidence of TE,
  • Safe discontinuation of primary anticoagulation,
  • Persistent and significant improvement in symptoms and quality of life, with no evidence of intolerance or refractoriness,
  • Transfusion independence in the majority of patients and significant reductions in the number of units transfused for those still requiring transfusions.
  • These results confirm the long-term safety and efficacy of continuous eculizumab treatment and demonstrate the impact of eculizumab on quality of life, reduction in PNH-related morbidities

Patient Characteristics (N = 153)
  • Female: 77 (50.3%)
  • Median age at diagnosis: 34 (range; 12–80)
  • Median age at commencement of eculizumab: 42 (range, 14–84)
  • Concomitant immunosuppression: 25 (16.3%)
  • Concomitant anticoagulation: 93 (60.8%)
  • LDH level: 2302 IU/L (range, 151–10300)

Authors: Anita Hill, MBChB, PhD, Richard J. Kelly, MBChB, Austin G. Kulasekararaj, MBBS, MD, Shreyans A. Gandhi, MBBS, MD, Lindsay D. Mitchell, MBChB, Modupe Elebute, MBChB, MD, Stephen John Richards, PhD, Matthew Cullen, MSc, Louise M. Arnold, RN, BSc, Joanna Large, RN, BSc, Alexandra Wood, RN, BSc, Gemma L. Brooksbank, RN, BSc, Tracy Downing, Claire McKinley, BSc, Dena Cohen, BSc, MSc,
Walter M. Gregory, PhD, Judith C. W. Marsh, MD, PhD, Ghulam J. Mufti, MD, Peter Hillmen, MBChB, PhD

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Eculizumab Protects Against Thromboembolism and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Conclusions
  • This analysis of a large international cohort of patients with PNH treated in clinical practice showed that eculizumab is associated with reduced risk of TE and mortality.
  • Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality.
  • Risk of TE was also increased in patients with hepatic dysfunction and the presence of headache and dyspnea at enrollment.
  • Older age and lower Karnofsky performance score at enrollment, along with BMT during follow-up, were associated with a significantly higher risk of mortality. 
  • Administration of eculizumab resulted in reductions in the cumulative incidence of TE and mortality at both 1 and 2 years and had a significant effect against TE and premature mortality in patients with PNH.

Patient Characteristics (N=1047)
  • As of June 30, 2012, a total of 1547 patients from 25 countries on 5 continents enrolled in the International PNH Registry. 
  • A total of 1047 patients were eligible for analysis:
  • 536 patients 51.2%) were treated with eculizumab during follow-up.
  • 511 patients (48.8%) were untreated.

Authors: Gerard Socié, Hubert Schrezenmeier, Petra Muus, Jeff Szer, Alvaro Urbano-Ispizua, Jaroslaw P. Maciejewski, Robert Brodsky, Monica Bessler, Yuzuru Kanakura, Wendell Rosse, Gus Khursigara, Camille Bedrosian, Peter Hillmen

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Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival

Patients and investigations
Seventy-nine patients with PNH were treated with eculizumab at Leeds Teaching Hospitals PNH center between May 2002 and July 2010, including 34 patients from the clinical trials and a further 45 treated since then. 

Funding was through the National Health Service either via central commissioning in England or local funding in Wales or Scotland. The follow-up of patients was approved through the Central Research Ethics Committee, and all patients gave signed informed consent for entry into the study in accordance with the Declaration of Helsinki. 

The diagnosis was established or confirmed using multicolor flow cytometry of the erythrocytes and granulocytes in all cases. Patients were assessed at a minimum of every 12 weeks by the Leeds PNH team. Data collected for analysis include age and symptoms at diagnosis, presence of a history of preceding aplastic anemia (AA) or myelodysplasia (MDS), age at the start of eculizumab, use of other medication to treat PNH, the occurrence of thrombosis before and during eculizumab treatment, blood transfusion requirement for the 12 months before starting eculizumab and after its initiation, lactate dehydrogenase (LDH) levels at the start of eculizumab and the most recent level (all of which were from May, June, or July 2010), and documentation of cause and date of death if applicable. Data were collected up until the end of July 2010 when this planned analysis was made.

In the 7 years before the availability of eculizumab, 30 patients who fulfilled our criteria for eculizumab therapy were cared for in Leeds. The mortality of these patients, up to the point at which they went on to receive eculizumab, was evaluated to provide a control group for comparison.

Authors: Anita Hill, Louise M. Arnold, Gemma L. Brooksbank, Stephen J. Richards, Matthew Cullen, Lindsay D. Mitchell, Dena R. Cohen, Walter M. Gregory, and Peter Hillmen

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Figure 1: Overall survival of 79 patients from initiation of eculizumab treatment compared with an age- and sex-matched normal population.
Figure 3: Overall survival of patients before and after eculizumab.
Figure 4: Blood transfusion requirements in the 12 months before eculizumab therapy and the most recent 12 months on eculizumab treatment in 64 patients.