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Velaglucerase alfa for type 1 Gauchers disease August 2009

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					                  Velaglucerase alfa
            for type 1 Gaucher’s disease

                                   August 2009




         This technology summary is based on information available at the time of research
and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or
  effectiveness of the health technology covered and should not be used for commercial purposes.



               The National Horizon Scanning Centre Research Programme is part of the
                                National Institute for Health Research
August 2009                                              National Horizon Scanning Centre
                                                      News on emerging technologies in healthcare


              Velaglucerase alfa for type 1 Gaucher’s disease
Target group
   •    Type 1 Gaucher’s disease – long term enzyme replacement therapy (ERT).

Background
   Type 1 Gaucher’s disease is a non-neuronopathic, inheritable, autosomal recessive
   disorder caused by insufficient activity of the enzyme glucocerebrosidase which is
   responsible for metabolising lipids called glucocerebrosides. The accumulation of
   glucocerebroside in lysosomes of macrophages gives rise to Gaucher cells which occur
   throughout the liver, spleen, bone marrow, skeleton and occasionally the lung. The
   resulting symptoms include enlarged liver and spleen (hepatosplenomegaly), anaemia,
   thrombocytopenia causing fatigue, discomfort, infections, bleeding and bruising, bone
   problems and other problems such as lung disease, impaired growth and delayed
   puberty 1,2 .

    Type 1 is the most common form of Gaucher’s disease and is usually distinguished from
    types 2 and 3 by a variable age of onset and an absence of neurological symptoms, though
    a proportion of people with type 1 Gaucher’s do have neurological deficits 3 . Type 1
    Gaucher’s varies in severity due to varying residual enzyme activity, ranging from mild
    asymptomatic cases (which may go undiagnosed) to severe, life threatening disease. Early
    onset in type 1 disease predicts a more aggressive course. Patients with the milder forms
    of type 1 may have a normal life expectancy, while untreated severe type 1 disease may
    lead to death from thrombocytopenic bleeding, asthenia or the complications of
    splenectomy within the first decade of life 4 .

Technology description
   Velaglucerase alfa (brand name not yet determined) is a recombinant form of
   glucocerebrosidase – an investigational ERT. Velaglucerase alfa is a gene-activated
   protein which is produced in a human cell line, and has an identical amino acid sequence
   to the naturally occurring enzyme.
   It is administered by intravenous (IV) infusion at 60 U/kg (15-60 U/kg in clinical trials)
   every two weeks.

Innovation and/or advantages
    Velaglucerase is intended to offer an additional treatment option for people with type 1
    Gaucher’s disease and for those who are intolerant or unresponsive to current therapies.

Developer
   Shire Human Genetic Therapies (HGT).

Availability, launch or marketing dates, and licensing plans:
   Velaglucerase alfa is a designated orphan drug in the EU and USA. It is currently in
   phase III trials.

NHS or Government priority area:
  No NHS or government priority area was identified.




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August 2009                                                  National Horizon Scanning Centre
                                                           News on emerging technologies in healthcare

Relevant guidance
    •  Clinicians of Addenbrooke’s Hospital, Cambridge and The Royal Free Hospital for
       the National Specialist Commissioning Agency. UK National Guideline for Adult
       Gaucher Disease. 20054.

Clinical need and burden of disease
    Gaucher’s disease is a rare condition and the most prevalent of the lysosomal storage
    diseases. Over 90% of affected individuals have type 1 Gaucher’s disease with an
    estimated prevalence of 1 in 200,0003 equating to approximately 270 people in England
    and Wales. There are an estimated 10 new diagnoses per year1.

Existing comparators and treatments
    The UK National Guideline for Adult Gaucher’s Disease4 recommends the following
    treatment options:

    Enzyme replacement therapy (ERT):
       • Imiglucerase (Cerezyme) – a modified form of human acid β-glucocerebrosidase
         produced through recombinant DNA technology using mammalian Chinese
         hamster ovary (CHO) cell culture.
       • Aglucerase (Ceredase) – no longer licensed for use. There is a limited residual
         supply for those patients unable to tolerate Cerezyme. The supply is unlikely to
         continue long term.

    Substrate reduction therapy:
       • Miglustat (Zavesca) – an oral daily therapy indicated for patients with mild to
           moderate Gaucher’s disease for whom ERT is not suitable.

    Supportive therapy is indicated for all patients and may include management of
    symptoms with blood products, bisphosphonate therapy, and/or analgesia.

    Patients identified with a Gaucher’s disease mutation, who may be asymptomatic and do
    not require treatment at present, are monitored for disease progression at which time
    treatment options will be reviewed.

Efficacy and safety

Trial              NCT00430625 5 (TKT032);                 NCT00553631 6 (HGT-GCB-039);
                   velaglucerase alfa; phase III.          velaglucerase alfa vs imiglucerase;
                                                           phase III.
Sponsor            Shire HGT.                              Shire HGT.
Status             Completed, unpublished 7 .              Ongoing.
Location           Latin America, Israel, Russian          EU (inc UK), USA and other
                   Federation, Tunisia.                    countries.
Design             Randomised, dose comparison,            Randomised, controlled, double-blind.
                   uncontrolled.
Participants and   n=24; type 1 Gaucher’s disease, age ≥   n=32; type 1 Gaucher’s disease, age ≥
schedule           2 years; Gaucher disease-related        2 years; treatment naive; Gaucher
                   anaemia, moderate splenomegaly,         disease-related anaemia, moderate
                   thrombocytopenia, palpable enlarged     splenomegaly, thrombocytopenia,
                   liver.                                  palpable enlarged liver.
                   Randomised to velaglucerase alfa IV     Randomised to velaglucerase alfa IV
                   45 U/kg or 60 U/kg every other week     60 U/kg or imiglucerase IV 60 U/kg

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August 2009                                                             National Horizon Scanning Centre
                                                                    News on emerging technologies in healthcare

                      for 12 months.                                every other week for 9 months.
Follow-up             12 months treatment period.                   9 months treatment period.
Primary               Change in haemoglobin concentration.          Change in haemoglobin concentration.
outcome
Secondary             Safety profile (platelet counts, spleen       Comparison of disease-specific
outcomes              and liver volumes, CCL18 and                  biomarkers.
                      chitotrioside biomarkers), quality of
                      life.
Key results           Both 45U/kg and 60U/kg: statistically         -
                      significant (p<0.0001) improvements
                      in mean haemoglobin concentration,
                      platelet and spleen sizes vs baseline;
                      reduction in liver volume.
Expected              Positive results reported in company          Q4 2009.
reporting date        press release in early August 2009. To
                      be presented at a scientific meeting Q4
                      2009.

Trial                 NCT00478647 8 (TKT034);                       NCT00635427 9 (HGT-GCB-044);
                      velaglucerase alfa after imiglucerase;        velaglucerase alfa open-label
                      phase III.                                    extension; phase III.
Sponsor               Shire HGT.                                    Shire HGT.
Status                Ongoing.                                      Ongoing.
Location              EU (inc UK), USA, Israel.                     EU (inc UK), USA and other
                                                                    countries.
Design                Non-randomised, open-label,                   Non-randomised, open-label,
                      uncontrolled.                                 uncontrolled.
Participants and      n=40; type 1 Gaucher disease, age≥2           n=102; completed study TKT032,
schedule              years; previously treated with                HGT-GCB-039 or TKT034.
                      imiglucerase.                                 Received velaglucerase alfa IV 15-60
                      Received velaglucerase alfa IV 15-60          U/kg every other week.
                      U/kg every other week for 12 months.

Follow-up             Until commercially available or patient       Until commercially available or patient
                      discontinuation.                              discontinuation.
Primary               Safety profile.                               Safety profile.
outcome
Secondary             Comparison of disease-specific                Haematological parameters and
outcomes              biomarkers.                                   organomegaly.
Expected              Q4 2009.                                      Unknown.
reporting date

Potential or intended impact – speculative
Patients
         Reduced morbidity                   Reduced mortality or increased      Improved quality of life for patients
                                             length of survival                  and/or carers
         Quicker, earlier or more accurate   Other:                               None identified
         diagnosis or identification of
         disease

Services
         Increased use                       Service reorganisation required     Staff or training required

         Decreased use                       Other:                               None identified


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August 2009                                                          National Horizon Scanning Centre
                                                                  News on emerging technologies in healthcare

Costs
        Increased unit cost compared to    Increased costs: more patients      Increased costs: capital
        alternative                        coming for treatment                investment needed
        New costs:                         Savings:                             Other: no additional costs


References
1
  Connock M, Burls A, Frew E et al. The clinical effectiveness and cost-effectiveness of enzyme
   replacement therapy for Gaucher’s disease: a systematic review. Health Technology Assessment 2006;10(24):
  1-149.
2
  Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. The Lancet. 2008;372(9645):1263-
   71.
3
  Capablo JL, Saenz de Cabezo´n A, Fraile J et al. Neurological evaluation of patients with Gaucher disease
   diagnosed as type 1. Journal of Neurology, Neurosurgery and Psychiatry 2008;79:219–222.
4
  UK National Guideline for Adult Gaucher Disease. Deegan P, Hughes D, Mehta A et al. Department of Health
   National Specialist Commissioning Advisory Group. August 2005.
5
  ClinicalTrials.gov. A study of GA-GCB enzyme replacement therapy in Gaucher disease.
   http://www.clinicaltrials.gov/ct2/show/NCT00430625 Accessed 15 July 2009.
6
  ClinicalTrials.gov. Study of Gene-Activated® Human Glucocerebrosidase (GA-GCB) ERT compared with
   imiglucerase in type I Gaucher disease. http://www.clinicaltrials.gov/ct2/results?term=NCT00553631
  Accessed 15 July 2009.
7
  Shire press release 3rd August 2009. Shire reports positive results from first of three phase III trials of
   velaglucerase alfa for Type 1 Gaucher disease and provides important updates on interactions with FDA.
   http://www.shire.com/shire/NewsAndMedia/News/showShirePress.jsp?ref=1031&tn=3&m1=8&m2=20
   Accessed 18 August 2009.
8
  ClinicalTrials.gov. Study of GA-GCB enzyme replacement therapy in type 1 Gaucher disease patients
   previously treated with imiglucerase. http://www.clinicaltrials.gov/ct2/results?term=NCT00478647 Accessed
  15 July 2009.
9
  ClinicalTrials.gov. An open-label extension study of GA-GCB ERT in patients with type 1 Gaucher disease.
   http://www.clinicaltrials.gov/ct2/results?term=NCT00635427 Accessed 15 July 2009.




   The National Institute for Health Research National Horizon Scanning Centre Research
                     Programme is funded by the Department of Health.
The views expressed in this publication are those of the author and not necessarily those of the
                        NHS, the NIHR or the Department of Health

                              The National Horizon Scanning Centre,
                          Department of Public Health and Epidemiology
              University of Birmingham, Edgbaston, Birmingham, B15 2TT, England
                        Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269
                           www.pcpoh.bham.ac.uk/publichealth/horizon

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