Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
SBU evaluation of biosimilars: measurement of antibodies
Author
Year
Reference
Buzi et al
1989
(1)
GH brand
Patients
Study
Ab to hGH method
Humatrope
(1989)
GHD
1 year study
Comparison two
methods, inhouse
and Sportsman et al
Results
antihGH titer
Binding capacity
Positive
control
Three children
positive by both
methods had
0.05 mg/L
Classification
AEs
3/20 positive
method 1,
9/20 method
2
0.12 mg/L
3.8 mg/L
Cardoso et al
1993
(2)
MillsGH
Somatonorm
Saizen
(1993)
GHD
Randomly
selected
patients from
several studies
In house method
Positve
binding in
40%, 70% and
7,7% resp.
Chang et al
1991
(3)
Chatelain et al
1994
(4)
Saizen
(1991)
GHD
5 patients for
one year
Zeisel method
One patient
positive
Sanofi 1994
SGA
2 year two
doses, 6 months
placebo 95
children
Sanofi in house
method details
provided
Not reported
Not reported
Not
reported
Max binding
5.9% 1pat16 ,
2-3%, 1-2% in
76 children
Weak ECP ab
Painful
injections
skin
erythema
18pats
Sida 1 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Chihara et al
2006
(5)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Positive
control
Classification
AEs
Genotropin
2006
AGHD
Multicentre
double-blind
placebo 37:36
24 weeks dose
escalation
In house method at
start and 24 weeks
Not reported
Not reported
Not
reported
Not reported
Oedema
21%
De Bellis et al
2006
(6)
No treatment
(2006)
ISS
119 GHD, ISS or
acquired GHD,
40 controls
Fine et al
1994
(7)
Nutropin 1994
CRI
Fine et al
1995
(9)
Nutropin 1995
CRI
Multicentre
placebo
controlled
double-blind
Multicentre
placebo 125
children, 2 year
study
Amman 1985 (8)
19/82 patients
low titer
Not reported
Not
reported
Method not
described samples
taken at 3 month
intervals
Not reported
Not reported
Not
reported
Circulating
antibodies
identified to
pituitary GH
producing
cells found in
21/60
children
Not reported
Not reported
Low not
reported
Sida 2 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
FjellestadPaulsen et al
1998
(10)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Saizen 1998
SGA
Open
comparative
multicentre trial
101 children at
least 3 years
treatment and
follow-up
Zeisel
5 children
positive very
low titres. I
child still
positive at
36mths
Not possible to
measure
Fryklund et al
1986
(11)
Somatonorm
(1986)
GHD
Three
Kabi method
consecutive Kabi
studies showing
effect of
purification
Titre > 4 in 6
patients
0,66mg/L
Girard et al
1986
(12)
Hou et al
2009
(13)
Somatonorm
and
Crescormon
(1986)
GHD
Jintropin aqua
In
Chinese2009
GHD
21 children in
double blind
treatment study
12 months open
label
Study III 6/36
low titres
Kabi method
described in detail
Anti E.coli protein
antibody method as
well
Not described
measured at 3
month intervals
No results
shown in
abstract, main
text in Chinese
Positive
control
Classification
AEs
Titres and
binding
capacity
decreased
when E coli
proteins were
removed by
purification
0,24mg/L
0,01mg/L
I child with binding
capacity 0.44mg/L
otherwise <0.2mg/L
in 50% of children
Not
reported
Not reported
Not
reported
Not reported
Not reported
Sida 3 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Jones
2002
(14)
GH brand
Patients
Protropin
(2000)
Rhesus
monkey
Lopez-Siguero
et al
2011
(15)
Omnitrope
liquid pen
injector
2011
GHD
Massa et al
1993
(16)
Somatonorm
switch to
Genotropin
(1993)
Mauras et al
2000
(17)
Nutropin
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Positive
control
Genentech in house
method
Ph III 70 naïve
children 5 years
single arm
In house methodgel electrophoresis
GHD
Switch patients,
5 year follow up
GHD
2 dose study
12 months in 97
patients near to
final height
Classification
AEs
Antibodies
decrease as
product is
more purified
Not reported
Not reported
Kabi Method
described
See figure 1
and table
See figure 2
In house method 3
month intervals,
Titres greatest
at baseline
declined
during study,
All samples <2 mg/L
Not
reported
Western blot, nonquantitative
Descriptive 2
of 70 anti
hGH 10 /70
antiECP
Eosinophil
count
increase
Titers
decreased
after switch
Not
reported
Results
similar in
both groups,
no details of
how many, or
percent
3 cases of
eosinophilia
Sida 4 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Peter et al
2012
(18)
GH brand
Patients
Study
Ab to hGH method
Genotropin
and LB03002
depot (2012)
GHD
Daily vs once a
week
multicentre
study in 11
centre in Europe
3 year study 51
patients
Central lab
measurements, no
details, anti-yeast ab
as well
Peterkova et al
2007
(19)
Valtropin and
Humatrope
GHD
Double blind
12 months
MDs Pharma
Hamburg
Results
antihGH titer
Not reported
Binding capacity
Positive
control
Classification
AEs
Not reported
Not
reported
Positive ab
results in 14
patients in
higher depot
dose and
once only in
both low
dose groups
none in
Genotropin
group yeast
antibodies
seen as well
42/51
reported
319AEs, pain
at injection
site in depot
patients
Low binding capacity
yeast proteins in
4/70 Valtropin
Not
reported
3/70
Valtropin had
ab, 1/18 in
Humatrope,
no details
provided
Sida 5 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Pitukcheewano
nt et al
2002
(20)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Protropin
Nutropin
(2002)
GHD
Single patient
who resumed
growth after
washout
Genentech
4.5
6.0 mg/L
3.9
<2
Quigley et al
2002
(21)
Humatrope
Turners
232 pats
Randomized
study 5
treatment
groups
232 patients
9 year study, GH
and oestrogen
Anti GH and anti
Ecoli measured at 3
month intervals first
18 months at 24
months, then once a
year
No data
No data
Rasmussen et al
1989
(22)
Norditropin
GHD
197 patients,
90 transferred
from
Somatonorm
therapy
In house
radioimmuno assay
3 patients with
low titres
Positive
control
Classification
AEs
Neutralizing
antibody.
Growth
resumed after
change to
Nutropin
No data
+
No data
Otitis and
other AE
expected in
this group
Injection site
reaction to
metacresol
change to
benzyl
alcohol
Sida 6 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Reiter et al
2001
(23)
RekersMombarg et al
1995
(24)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Nutropin plus
Nutropin
depot
GHD
Naïve
patients12
months two
arms74 patients
Genentech in house
radioimmunoprecipitation assay
assays at 3 month
intervals
16 (44%) in
high dose and
28 (68%) in
low dose
depot low titre
antibodies
Immunogenicity
parameters 34 +
16 children
5 years
reference group
comparison
no
no
Humatrope
1995
ISS
Positive
control
Classification
AEs
Antibody binding
Not
capacity measured at reported
titre 1 or more. No
patient had a binding
capacity above
2 mg/L
No
attenuation
of growth
rate no
relation to
binding
capacity
Injection site
reactions
no
Immune
system in
general
leucocytes
and
lymphocytes
transient
decrease,
nadir 6
months
no
Lower
growth rate
than with
once daily
treatment
Sida 7 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Romer 2007 et
al
(25)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Positive
control
Classification
Omnitrope
liquid,
Omnitrope
powder
Genotropin
GHD
naïve
And
treated
Comparative
Study
Sandoz in house
method
Not reported
Not reported
Not
reported
Positive in
Omnitrope
powder
patients
Genotropin vs
Omnitrope
AEs
Reduced after
further
purification
Omnitrope vs
Omnitrope liq
Romer et al
2009
(26)
Omnitrope
liquid
GHD
Phase III
comparision 189
patients
Sandoz in house
assay
3 more
patients
developed low
titer after
switch to
Omnitrope
Not reported
Not
reported
One of 45
treated with
Genotropin
positive. At
final visit no
patients had
GH ab.
Rosenfeld et al
1986
(27)
Protropin
Somatrem
(1986)
Turner
67 patients
treated for one
year, two
groups one with
oxandrolone
and GH, other
GH alone
In house method
described in detail,
titres and binding
capacity defined
13/34 patients
with positive
ab titers
Only one patient
with binding capacity
>1mg/L, slow growth
in this patient in the
growth hormone
Negative
control
used
slow growth
in this patient
in the growth
hormone
treatment
only arm
Sida 8 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Shih et al
1994
(28)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Positive
control
Classification
Genotropin
Humatrope
and Saizen
(1994)
GHD
1 year
comparative
study, 5 patients
in each group
Zeisel method
Not reported
Not reported
Not
reported
1 child on
Saizen
developed
antibodies
Sportsman et al
1989
(29)
Humatrope
GH
Immunoassay
methodology
for anti GH
assays
automation and
computer
analysis
described
Humatrope in house
method described in
detail
Yes
Yes
Yes
Titres binding
capacity
binding
constants and
validation
discussed in
detail
Suh et al
1995
(30)
Protropin
(1995)
GHD
Single patient
NIH method
Wit et al
1995
(31)
Somatonorm
then
Genotropin
(1995)
ISS
27 children
Method not
described
Depot/
growth
promoting
effect of
antibodies
4.63–5 nanomoles/L
High titre
(undefined) in
one patient
Not reported
AEs
Not
reported
Slow growth
in that
patient
Sida 9 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
Author
Year
Reference
Wit et al
1989
(32)
GH brand
Patients
Study
Ab to hGH method
Results
antihGH titer
Binding capacity
Positive
control
Classification
Somatonorm
(1989)
ISS
same gp
as in 17
30 children one
year treatment
Method not
described
Patient 25
high titre of
GH antibodies
Not reported
Not
reported
Slow growth
therapy
stopped after
9 months
treatment
Wit et al
1989
(33)
Somatonorm
(1989)
ISS
same gp
as in 17
30 children one
year, 18 in
treatment arm,
12 in untreated
group
Hospital method %
binding
Binding o
16.7%
considered
positive
Patient 25 had
binding capacity of
8.6 U/L at 9 months
and weak binding
Not
reported
Slow growth
in patient 25
304GHD, 91
Turner up to 54
months
Zeisel method actual
reference
Zeisel et al
1992
(34)
Saizen
(1992)
GHD
Turner
Anti Ecoli
meansured by ELISA
AEs
6 children with
low levels
0.01 mg/L to
0.1 mg/L
9 GHD
produced ab
No Turner ab
1. No method description
2. Repeat of similar studies with the same GH preparation
3. Not relevant patient group
Sida 10 av 13
Appendix 2
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
1.
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experience in the United Kingdom. Clinical endocrinology. 1989;30(5):531-8.
2.
Cardoso AI, Llera AS, Iacono RF, Domene HM, Martinez AS, Heinrich JJ, et al. Heterologous humoral immune response in patients treated with human growth
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3.
Chang TC, Kuo HF, Liu PC, Shih KC, Zeisel HJ, Ho LT. Recombinant DNA produced somatropin in the treatment of prepubertal growth hormone deficient children.
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Chatelain P, Job JC, Blanchard J, Ducret JP, Olivier M, Sagnard L, et al. Dose-dependent catch-up growth after 2 years of growth hormone treatment in intrauterine
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Chihara K, Kato Y, Kohno H, Takano K, Tanaka T, Teramoto A, et al. Efficacy and safety of growth hormone (GH) in the treatment of adult Japanese patients with GH
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De Bellis A, Salerno M, Conte M, Coronella C, Tirelli G, Battaglia M, et al. Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with
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Fine RN, Kohaut EC, Brown D, Perlman AJ. Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter
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Fine RN, Attie KM, Kuntze J, Brown DF, Kohaut EC. Recombinant human growth hormone in infants and young children with chronic renal insufficiency. Genentech
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hormone in the treatment of short stature in young children with intrauterine growth retardation. Acta paediatrica (Oslo, Norway : 1992). 1998;87(5):511-7.
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Fryklund LM, Bierich JR, Ranke MB. Recombinant human growth hormone. Clinics in endocrinology and metabolism. 1986;15(3):511-35.
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Girard F, Gourmelen M. Clinical experience with Somatonorm. Acta paediatrica Scandinavica Supplement. 1986;325:29-32.
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Jones AJ. The use of an animal immunogenicity model in the development of Protropin somatrem (methionyl human growth hormone). Developments in biologicals.
2002;109:107-18.
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Lopez-Siguero J, Borras Perez MV, Balser S, Khan-Boluki J. Long-term safety and efficacy of the recombinant human growth hormone Omnitrope(R) in the treatment
of Spanish growth hormone deficient children: results of a phase III study. Advances in therapy. 2011;28(10):879-93.
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Massa G, Vanderschueren-Lodeweyckx M, Bouillon R. Five-year follow-up of growth hormone antibodies in growth hormone deficient children treated with
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Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases
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Peter F, Bidlingmaier M, Savoy C, Ji HJ, Saenger PH. Three-year efficacy and safety of LB03002, a once-weekly sustained-release growth hormone (GH) preparation, in
prepubertal children with GH deficiency (GHD). The Journal of clinical endocrinology and metabolism. 2012;97(2):400-7.
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Peterkova V, Arslanoglu I, Bolshova-Zubkovskaya E, Romer T, Zdravkovic D, Kratzsch J, et al. A randomized, double-blind study to assess the efficacy and safety of
valtropin, a biosimilar growth hormone, in children with growth hormone deficiency. Hormone research. 2007;68(6):288-93.
20.
Pitukcheewanont P, Schwarzbach L, Kaufman FR. Resumption of growth after methionyl-free human growth hormone therapy in a patient with neutralizing
antibodies to methionyl human growth hormone. Journal of pediatric endocrinology & metabolism : JPEM. 2002;15(5):653-7.
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Quigley CA, Crowe BJ, Anglin DG, Chipman JJ. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final
height. The Journal of clinical endocrinology and metabolism. 2002;87(5):2033-41.
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Rasmussen LH, Zachmann M, Nilsson P. Authentic recombinant human growth hormone. Results of a multicenter clinical trial in patients with growth hormone
deficiency. Helvetica paediatrica acta. 1989;43(5-6):443-8.
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Reiter EO, Attie KM, Moshang T, Jr., Silverman BL, Kemp SF, Neuwirth RB, et al. A multicenter study of the efficacy and safety of sustained release GH in the
treatment of naive pediatric patients with GH deficiency. The Journal of clinical endocrinology and metabolism. 2001;86(10):4700-6.
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Rekers-Mombarg LT, Rijkers GT, Massa GG, Wit JM. Immunologic studies in children with idiopathic short stature before and during growth hormone therapy. Dutch
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Romer T, Peter F, Saenger P, Starzyk J, Koehler B, Korman E, et al. Efficacy and safety of a new ready-to-use recombinant human growth hormone solution. Journal of
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Romer T, Saenger P, Peter F, Walczak M, Le Bouc Y, Khan-Boluki J, et al. Seven years of safety and efficacy of the recombinant human growth hormone Omnitrope in
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Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review
27.
Rosenfeld RG, Hintz RL, Johanson AJ, Brasel JA, Burstein S, Chernausek SD, et al. Methionyl human growth hormone and oxandrolone in Turner syndrome:
preliminary results of a prospective randomized trial. The Journal of pediatrics. 1986;109(6):936-43.
28.
Shih KC, Ho LT, Kuo HF, Chang TC, Liu PC, Chen CK, et al. Linear growth response to recombinant human growth hormone in children with growth hormone
deficiency. Zhonghua yi xue za zhi = Chinese medical journal; Free China ed. 1994;54(1):7-13.
29.
Sportsman JR, Smith WC, Winely CL. Practical automation and interpretation of quantitative assays of antibodies to therapeutic proteins, illustrated with human
growth hormone. Clinical chemistry. 1989;35(8):1623-30.
30.
Suh BK, Jorgensen EV, Root AW. Facilitation of the growth promoting effect of growth hormone (GH) by an antibody to methionyl-GH. Journal of pediatric
endocrinology & metabolism : JPEM. 1995;8(2):97-102.
31.
Wit JM, Boersma B, de Muinck Keizer-Schrama SM, Nienhuis HE, Oostdijk W, Otten BJ, et al. Long-term results of growth hormone therapy in children with short
stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group. Clinical endocrinology.
1995;42(4):365-72.
32.
Wit JM, Fokker MH, de Muinck Keizer-Schrama SM, Oostdijk W, Gons M, Otten BJ, et al. Effects of two years of methionyl growth hormone therapy in two dosage
regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues. (Dutch Growth Hormone
Working Group). The Journal of pediatrics. 1989;115(5 Pt 1):720-5.
33.
Wit JM, Rietveld DH, Drop SL, Oostdijk W, Gons M, Otten BJ, et al. A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature,
subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group. Acta paediatrica Scandinavica.
1989;78(3):426-35.
34.
Zeisel HJ, Lutz A, von Petrykowski W. Immunogenicity of a mammalian cell-derived recombinant human growth hormone preparation during long-term treatment.
Hormone research. 1992;37 Suppl 2:47-55.
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