Case Study 10. Improving lives and transforming services for Paroxysmal Nocturnal Haemoglobinuria (PNH), a life-threatening, disabling blood disorder
Submitting InstitutionUniversity of Leeds
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences, Public Health and Health Services
Summary of the impact
Eculizumab has transformed quality of life and life expectancy for
patients with PNH and led to major economic impacts with global drug sales
of $1,134 million in 2012 and to Alexion Pharmaceuticals being worth over
$19 billion. PNH is a disabling blood disorder that was previously fatal
in 50% of patients but with eculizumab survival is comparable to the
normal population as well as returning patients to having a normal quality
of life. Research in Leeds led to the introduction of eculizumab in 2007.
Eculizumab is now approved for clinical use in over 40 countries and for
another life threatening disease, atypical haemolytic uraemic syndrome.
Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired
haemolytic anaemia affecting approximately 5 people per million
population, most frequently occurring in early adulthood, is associated
with severe life-long symptoms and results in death in half of patients.
Peter Hillmen qualified in Medicine from the University of Leeds in 1985
and was awarded a PhD for his research into PNH in 1995. Hillmen
was appointed as a Consultant Haematologist in Leeds and Honorary Senior
Lecturer with the University of Leeds in 1996. He became Honorary
Professor in 2008 and the Chair of Experimental Haematology in 2013. In
1995 Hillmen published the "Natural History of PNH" demonstrating
that approximately 50% of patients died of PNH.1 In 1997
Alexion Pharmaceuticals developed eculizumab, an inhibitor of the
complement component C5, and commenced trials in autoimmune disorders.
In the early 1990's Hillmen had confirmed the importance of
complement, a system of proteins that form part of innate immunity, in the
destruction of PNH blood cells leading to the features, complications and
deaths in PNH. This made Hillmen realize that anti-complement
therapy, such as eculizumab, should be extremely effective in PNH. Hillmen
had continued PNH research after returning to Leeds in 1994, published
several papers and developed a PNH clinic. In 1999 Hillmen
approached Alexion to request eculizumab to perform a clinical trial in
PNH. The initial approach to Alexion to run a clinical trial was rejected
due to concern over patient numbers for this rare disease. However Hillmen
continued persuading Alexion to permit him to perform the trial and
towards the end of 2001 the initial Pilot study was approved.
Since 2002 Hillmen has supervised Leeds PhD students working on
PNH and including Dr Anita Hill from 2003 to 2006 (awarded a PhD in 2009)
and Dr Richard Kelly from 2007 to 2011 (PhD to be submitted 2013). Drs
Hill and Kelly were important in the clinical trials of eculizumab in PNH
and now both work within the PNH National Service led by Hillmen
and based in Leeds.
In May 2002 the Pilot study of eculizumab in 11 patients with PNH (9 in
Leeds) commenced with Hillmen as the Chief Investigator. The
results were dramatic leading to publication in the New England Journal of
Medicine in 2004.2 There were two subsequent Registration
trials of eculizumab in PNH (the TRIUMPH3 and SHEPHERD trials)
which Hillmen helped design, was the Chief Investigator for both
and recruited the largest number of patients. In total 195 patients were
recruited into the three Pivotal studies of eculizumab in PNH from 43
Centres worldwide and the Leeds contribution was 34 of these patients
(over double the next largest Centre). These trials confirmed the
impressive responses to eculizumab seen in the Pilot study leading to the
approval of eculizumab for clinical use in 2007 by the Food and Drug
Administration in the USA and the European Medicines Agency in Europe.
Subsequently eculizumab has been approved in over 40 countries for PNH and
was approved for atypical haemolytic uraemic syndrome (aHUS) by the FDA
and EMA in 2011. Eculizumab stopped the intravascular haemolysis in all
PNH patients and Hillmen subsequently demonstrated that the
complications of PNH, including thrombosis, renal failure and pulmonary
hypertension, were successfully treated. Subsequent publications from the
Leeds PNH group (Kelly, Hill, Hillmen) have demonstrated that the
survival of patients with PNH is normalised by eculizumab and that
patients can lead relatively normal lives.6
References to the research
 Hillmen P, Lewis SM, Bessler M, Luzzatto L and Dacie JV.
Natural history of paroxysmal nocturnal hemoglobinuria. (1995) New
England Journal of Medicine, 333, 1253-1258. 343 citations
Defined for the first time the dismal outcome for patients with PNH
 Hillmen P, Hall C, Marsh JCW, Elebute M, Bombara MP, Petro
BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF and Rother RP. Effect of
eculizumab on hemolysis and transfusion requirements in paroxysmal
nocturnal hemoglobinuria. (2004) New England Journal of Medicine,
350, 552-559. 176 citations
First description that targeted therapy with eculizumab was extremely
effective in PNH
 Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P,
Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A,
Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP
and Luzzatto L. The Complement Inhibitor eculizumab in paroxysmal
nocturnal hemoglobinuria. (2006) New England Journal of Medicine,
355, 1233-1243. 234 citations
Randomised trial proving that eculizumab is highly effective in PNH.
Ensured the drug was accepted and funded in many countries
 Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J,
Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler
M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement
inhibitor eculizumab on thromboembolism in patients with paroxysmal
nocturnal hemoglobinuria. (2007) Blood, 110, 4123-4128. 107
First demonstration that the main cause of death and a major cause of
illness in PNH, namely thrombosis, was effectively prevented and treated
 Risitano AM, Notaro R, Luzzatto L, Hill A, Kelly R, Hillmen P.
Paroxysmal nocturnal hemoglobinuria--hemolysis before and after
eculizumab. (2010) New England Journal of Medicine, 363,
2270-2272. 7 citations
Explanation for the continued transfusions for a minority of patient on
 Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M,
Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment
with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy
and improved survival. (2011) Blood, 117, 6786-6792. 29 citations
First convincing evidence that survival in PNH was normalized by
eculizumab. This led to it's approval and funding in many countries
Results of the eculizumab trials have been published in very high impact
journals and presented at numerous International Conferences including the
American Society of Hematology 2002 to 2012, the European Haematology
Association 2004 to 2011 and other conferences such as the Japanese
Society of Hematology, Brazilian Society of Hematology and the British
Society of Haematology by Hillmen.
Details of the impact
Leeds research has led to the introduction of a highly effective drug,
eculizumab, for PNH which has transformed patients lives, returned their
survival to normal, radically reconfigured care services and generated a
huge new pharmaceutical activity. Eculizumab is the only approved agent
for PNH in Europe, US, Canada, Japan and over 40 other countries and
research in Leeds played a critical role leading to these approvals [A].
Eculizumab was awarded the 2008 Prix Galien USA Award for Best
Biotechnology Product with broad implications for future biomedical
research and the 2009 Prix Galien France Award for Drugs for Rare
Diseases. Research led by Hillmen from Leeds has reached all patients with
this condition in the developed world and has demonstrated normalization
of overall survival for patients with PNH [A]. The impact on patients'
lives is highly significant and impacts the areas of (i) health and
welfare, (ii) commerce changing PNH from a disease that destroyed the
quality of life of patients, often young adults, leading to the death of
half of patients to one that is effectively managed with most patients
returning to a normal life.
PNH is a serious blood disorder found in 5 per million population with a
huge impact on quality of life with severe disabling lethargy, severe
intermittent abdominal pain, difficulty swallowing, erectile failure and
life-threatening thrombosis with half dying due to PNH. 3 per million are
severely affected requiring regular transfusions and usually being unable
to work and/or are dependent. Eculizumab immediately reverses the symptoms
and complications of PNH meaning that patients are able to return to work
and stop supportive therapies, such as transfusions and pain-killers.
Pregnancy is associated with very high maternal mortality (10% to 20%)
meaning that many patients wouldn't risk pregnancy. We have demonstrated
that eculizumab is safe in pregnancy and markedly reduces the risks with
many women having now had successful pregnancies. Eculizumab prevents the
complications of PNH meaning that patients can lead near normal lives
including working and contributing to society (6) [B, C, D, E]. This was
demonstrated in 195 patients from the clinical trials, 153 UK patients
managed by Hillmen and colleagues and through the Global PNH Registry
(currently over 2000 patients) and is Chaired by Peter Hillmen.
Approximately 3000 patients have received eculizumab since its initial
approval in 2007 including all eligible patients in the UK and global
sales suggest that this pattern is similar in all developed healthcare
Eculizumab has a clear, well-documented impact on survival in PNH as
demonstrated by Hillmen's group (Kelly et al., 20126).
Previously half of patients with PNH died within 10 years of diagnosis
with only 25% of patients surviving 25 years which, given the disease is
often diagnosed in early adulthood, has a profound impact. However
eculizumab normalizes survival in PNH (PNH registry data [F]) compared to
a 5 year mortality of approximately 35%.6 The spectre of PNH
for patients with virtually no quality of life and a high risk of early
death has now been lifted by the use of eculizumab [B-E] which has a high
public profile [G].
Guidelines and Governmental Approvals
PNH has now been nationally funded in many countries worldwide including
the Netherlands, France, Australia, Canada, and Japan as well as being
available in the US, Germany, etc. Since 2011 eculizumab has been approved
in the US, Europe and Canada for atypical Haemolytic Uraemic Syndrome
(aHUS), previously an untreatable condition leading to renal failure and
premature death. This approval would not have happened without the PNH
trials [A, B, C].
Changes in service configurations and disease regulation
As a result of our research PNH is designated as a highly specialised
service in England and funded as a National Service through the Advisory
Group for National Specialised Services (AGNSS) [H]. This covers the cost
of the Service (in excess of £1million/year) and the cost of eculizumab
for PNH (approximately £25million/year). The National PNH Service employs
15 people and contracts homecare nurses to deliver 4000 doses of
eculizumab by intravenous infusion in patients' homes each year.
The approval of eculizumab led to the establishment of the PNH Global
which has enrolled over 2000 patients with PNH. Hillmen chairs the
Executive Committee of the PNH Registry and Leeds has recruited over 250
patients being the largest Centre globally.
The approval of eculizumab for PNH has been an economic success for
Alexion Pharmaceuticals as their only approved drug [I]. The sales of
eculizumab in 2012 were $1.134 billion. This was highlighted in the
September 2012 edition of Forbes magazine in an article entitled: "How A
$440,000 Drug Is Turning Alexion Into Biotech's New Innovation Powerhouse"
[G]. The current estimated market capitalisation for Alexion is $19billion
making Alexion and the development of eculizumab one of the most
impressive economic successes in the last 10 years [J].
Sources to corroborate the impact
A) Regulatory approval of eculizumab for the treatment of PNH in the U.S,
E.U., Japan and other countries.
B) Australian Government Department of Health and Aging report entitled:
"Guidelines for the treatment of Paroxysmal Noctunrnal Haemoglobinuria
(PNH) through the Life Saving Drugs Program" published in December 2010
recommending the funding of eculizumab for PNH Nationally in Australia and
widely referencing researchers from Leeds including Hillmen, Hill and
C) All Wales Medicines Strategy Group Final Appraisal Report entitled:
"Eculizumab (Soliris) for the treatment of paroxysmal nocturnal
haemoglobinuria" was published in April 2009 with extensive references to
the work of Leeds researchers (Hillmen, Hill, Kelly). It
recommended that: "Eculizumab (Soliris®) is recommended for restricted use
within NHS Wales according to agreed guidelines for the treatment of
paroxysmal nocturnal haemoglobinuria."
D) Letters of support from leading international PNH clinicians
confirming the impact the research on PNH in Leeds led by Hillmen
has had on the lives of patients with PNH globally.
E) Letter of support from patients with PNH (one from UK and one from
Canada) confirming the dramatic impact eculizumab has had on their lives.
F) Changes in outcome in national figures for PNH documented from the
National Registry. Currently over 150 patients with PNH are on treatment
with eculizumab in the United Kingdom.
G) Extensive coverage in the national and international media (print,
electronic, radio and television; file available) involving Hillmen. This
includes the recent article in the Forbes magazine describes the impact of
eculizumab and Alexion Pharmaceuticals which extensively acknowledges the
central role of Hillmen. (http://www.forbes.com/sites/matthewherper/2012/09/05/how-a-
H) Service Specification and Standards 2012/13 - Paroxysmal Nocturnal
Haemoglobinuria Service. National Specialised Commissioning Team (NSCT).
I) Sales figures for eculizumab are available online
J) Letter of support from Dr Leonard Bell, Chief Executive Officer,
Alexion Pharmaceuticals Inc. confirming the central role Hillmen
played in the development of eculizumab for PNH.