HGH Presentation 150109

Evaluation of PEG-
hGH Failure
Available rhGH
Brands in USA
Name of hGH Approval Date Company Dosage Form Dosage OB Listed OB Listed Platform/
Brand Strength Exclusivity Patents
Accretropin 23.01.2008 Cangene Aqueous 5 mg/ml NP: Jan.23,2011 - E.coli
Serostim 23.08.1996 EMD Serono Lyophilized 6 mg/vial M-65 -
23.08.1996 5 mg/vial (HARS) Mammalian
HIV Associated Cell Line
25.07.1997 4 mg/vial Adipose (Mouse
06.09.2001 8.8 mg/vial redistribution C127)
syndrome
July 13,2010
Saizen 08.10.1996 5 mg/vial I-440 -
29.08.2000 8.8 mg/vial Replacement of
EGH in adults
with GHD
Zorbtive 01.12.2003 8.8 mg/vial ODE: -
Dec.01,2010
Tev-Tropin 04.01.2002 Ferring Lyophilized 5 mg/vial - - E.coli
Nutropin 17.11.1993 Genentech Lyophilized 5 mg/vial - US5096885/ E.coli
17.11.1993 10 mg/vial Mar.2009
Nutropin AQ 29.12.1995 Aqueous 10 mg/2 ml I-462: Idiopathic US5763394/
03.01.2008 Aqueous 5 mg/2 ml short stature June 2015
M-50: Effect on
03.01.2008 Aqueous 20 mg/2 ml VAT in AGHD
Nutropin AQ 22.04.2002 Aqueous 10 mg/2 ml
Pen
Name of hGH Approval Date Company Dosage Form Dosage OB Listed Exclusivity OB Listed Platform
Brand Strength Patents
Humatrope 08.03.1987 Eli Lilly Lyophilized 5 mg/vial M-45: Adults in GHD - E.coli
04.02.1999 6 mg/vial I-518: SHOX
Nov.2009
04.02.1999 12 mg/vial
04.02.1999 24 mg/vial
Nordiotropin 20.06.2000 Novo Nordisk Aqueous 5 mg/1.5 ml I-551:Turner's US5849700 E.coli
10 mg/ 1.5 ml syndrome;Sep.2010 Dec.2015
I-536: Noonan US5849704
15 mg/1.5 ml syndrome;May 2010 Dec.2015
Norditropin 01.10.2004 10 mg/ 1.5 ml I-572: SGA US5633352
Nordiflex 15 mg/1.5 ml Oct.2011 May 2014
(Pen) I-439:GHD
ODE: May 2014
Genotropin 24.08.1995 Pharmacia & Lyophilized 5.8 mg/vial I-496:Turner's US5435076 E.coli
23.10.1996 Upjohn 13.8 mg/vial syndrome who have (Apr.2013)
open epiphyses US5501673
Genotropin 27.01.1998 0.2-2.0 mg/vial Apr.2009 (Apr.2013)
(PF) 24.08.1995 1.5 mg/vial US5716338
(Feb.2015)
Valtropin 19.04.2007 LG Life Lyophilized 5 mg/vial NP: Apr.2010 S.
Sciences cerevisiae
Omnitrope 30.05.2006 Sandoz Lyophilized 1.5,5.8 mg/vial NP: May 2009 - E.coli
16.01.2008 Aqueous 5 mg/1.5 ml
25.08.2008 10 mg/1.5 ml
Current rhGH Market
Market 30/06/200 30/06/2007 % 30/06/2008 30/06/2007 %
8 Sales in Change Consumpti Consumpti Change
Sales in USD on in IU on in IU
USD
USA 1230.2M 1089.7M 12.9 79,755.8 76,267.3 4.6
EU 886.5M 755M 17.4 61906.6 59,464.5 4.1
Rest of 38.6M 34M 13.5 2,216.6 2,227 -0.5
Europe
Rest of 563.9M 524.7M 7.5 40,026.5 34,890.8 14.7
World
World 2719.2M 2403.5M 13.1 183,905.4 172,849.7 6.4
wide
Source: Newport Horizon Premium (IMS Database)

Market Share by Brand for hGH
1.9 billion USD glabal sales in 12 months of June 2006; Source: IMS Database;
From: Opportunities and Barriers in the Biosimilar market: Evolution or revolution for
Generics Complanies? By Pricewaterhouse Coopers LLP
Market Sales Value for 2007
(In Million USD)
371; 14%
627; 24%
Nutropin(Genentech)
Humatrope (Lilly)
440.8; 17%
Genotropin(Pfizer)
Saizen/Senstim(EMD)
290.5; 11%
Norditropin(Novo)
843; 33%
Source: Annual reports:2007

hGH
 HGH, a polypeptide of 191 amino acids
 Produced in the anterior pituitary gland
 Secreted mostly in sleep in pulsatile manner
 Acts directly or through IGF-I
 Released throughout the life span in variable modes in
different phases of life
 with higher secretion in childhood,
 Diminishes in adulthood
 Lowest in elderly
 Higher 24 hr. integrated GH serum concentrations in women
than men
hGH
 Essential stimulator of post-natal growth &
development
 Potent Anabolic hormone modulating
 Energy balance
 Lipid and protein metabolism
 Body composition, Body fluid control, Bone growth and
mineralization
 Cardiovascular function
 Mood, cognition, memory & learning, general well-being
Crystal Structure of hGH by Abdel-
Meguid and Coworkers
 Contains four α helices tightly packed as antiparallel
bundles aligned in up-up-down-down orientation;
 54% of GH's 191 aa are contained in these four α
helices
 Also contains a “large loop” between residues 33
and 75, a “smaller loop” between residues 129 and
154, and a “small loop” located at the carboxy
terminus
GH/GHR Dimerization
 GHR dimerization essential for GH action
 GH induces GHR dimerization followed by subsequent
internalization of GH/GHR complex and causing GH
induced intracellular signalling
 GH/GHR complex consists of
 One molecule of GH and two molecules of receptor
 Major binding determinants in Site 1 of GH molecule
 Located in 2 minihelices between α helices 1 and 2 and between the
center and carboxyl terminus of helix 4
 GHR Site 1 residues are amino acids 40 to 45 and 101 to 106, which
interact with GH amino acids 168 to 176 in α helix 4 and residues 60 to
63 in the second minihelix
 GHR Trp 169 interacts with hGH residues 171 to 179 in α helix 4
GH/GHR Dimerization
 Site 2 binding determinants in GHR
 Same as Site 1 except for Asn 218 especially Trp 104 and Trp
109
 Site 2 residues important for contact and dimerization
 Phe 1, Ile 4 and Asp 116 in third α helix
 Approaches to develop GH agonist with increased binding
affinity to GHR
 Altering Site 1
 By having GH analogues with residues altered in the C terminus of first
helix
FDA Approved Indications
Growth Hormone Disorders
 Growth hormone deficiency
 Pituitary disorder resulting in short stature and other
physical ailments
 Critical role of hGH in stimulating body growth and
development, production of muscle protein and
breakdown of fat, affecting numerous body processes
Adverse Effects of hGH
 Anti-GH Abs reported but no untoward effect on
GH
 Fluid retention and Carpal tunnel syndrome in adults
 Incidence of type 2 diabetes
 Idiopathic intracranial hypertension observed
occasionally but resolves with cessation of treatment
 Slipped capital femoral epiphysis
Growth Hormone Deficiency in Children: In Endocrinology (Fifth Edition) Vol.1,pp:747,

Elsevier publication
Adverse Effects of hGH
 Rare and unproven complications include:
 Acute pancreatitis
 Increased growth of pigmented nevi
 Prepubertal gynecomastia
 Important theoretical risk:
 Malignancy
 Leukemia
 Incidence and mortality due to
 Colonic cancer & Hodgkin's disease
Epidemiology of GHD
 Society of Endocrinology estimates:
 Prevalence is 3 in 10,000 of adult population
 With one third developing it in adult stage (AO-GHD)
 Varies between countries (numbers given/million)
 UK-100 to 200
 North Western Spain- 455
 France- 46
 Indian Journal of Pediatrics (Pharmabiz article)
 Incidence of GHD is around 1 in 4000 to 1 in 10,000
 Prevalence of GHD on rise in India
 Education on symptoms and implications low
Pegylated rhGH
Genentech
 PEG5000-hGH: No Development reported
 N-hydroxysuccinimide ester of 5 kda PEG5000 reagent
 Conjugation to primary amines, possible at N-terminal F
or ε-NH2 group of 9 lysines in hGH
 Reactivity: 4 general classes:
 α amine group of F (Phenyl alanine at N terminal) & ε-NH2
group of Lys-140: Most Reactive
 ε-NH2 group of Lys-145, Lys-38, Lys-70
 Lys-41, Lys-158, Lys-168, Lys-172
 Lys-115: Not Reactive
The Journal of Biological Chemistry: Vol.271, No.36, Issue of Sep. 6,1996; pp:21969-21977
Genentech
 Reactivity: 4 out of 9 lysines:
 Buried to some degree upon binding to two receptors
 3 buried in Site 1(Lys-41, Lys-168, and Lys-172): Not very
reactive;1 buried in Site 2 (Lys-115): Not reactive
 Potency studies carried out in young female
hypophysectomized rats & analysis of clearance in
young adult male Sprague-Dawley rats
 Administered 30 mcg/day/rat for 10 days or a single injection
of hGH (300 mcg) or PEG-5-hGH (180 mcg)
 Efficacy of pegylated analogs optimal for hGH conjugated
with 5 eq. of PEG5000 & 10 fold increase in potency
 Observed some disproportionate growth of some internal
organs including liver, spleen and thymus (No data reported)
The Journal of Biological Chemistry: Vol.271, No.36, Issue of Sep. 6,1996; pp:21969-21977
 Time Course of Clearance from Serum of hGH,
PEG-5-hGH derivatives or hGH in complex with 2
eq. Of the hGHBP after IV (Panel A) or SC (Panel
B) injection into rats
PFIZER INC.
 PFA-794428- Pegylated
hGH
 PEG Reagent:
 WO2005/079838
 FD: Jan.2005
 3986/DELNP/2006
 40 K branched butyral
dehyde PEG
 WO2006024953
 FD: Aug.2005
 1056/DELNP/2007
PFIZER INC.
 PHA-794428 for GHD: Discontinued in Phase II
 Cause: Lipoatrophy at injection site
 40 Kda PEG covalently linked to N-terminal
 PK/PD studies in humans following:
 Single S.C. Dose in the range of 10-500 mcg/Kg
 Single S.C. Dose of 3.6 mg (51 mcg/Kg)
 10 to 20 fold increase in AUC and serum half life
 Reduction in receptor affinity and reduced serum clearance
Vmax and Km for PHA-794428: 84 mcg/hr; 53 mcg/hr
 Vmax and Km for Somatropin: 104 mcg/hr; 3.6 mcg/hr
Source: Xenobiotica;2008- Oct.,38(10)1340-1351:Webster R., et al.:Department of
Pharmacokinetics, Pfizer Global Research and Development, Sandwich, UK
PFIZER INC.
 PHA-794428
 To Evaluate the Dose Response and Safety in Children
with GHD
 Age: 6 to 12 years
 Estimated Enrolment: 32
 Study Design: Double-blind Single Dose Study
 Study Start Date: June 2006
 Study Completion date: December 2007
 Study terminated: 10 December 2007
 Due to injection-site lipoatrophy
Source: NCT00314938: ClinicalTrials.gov

PFIZER INC.
 PHA-794428
 To Evaluate the Dose Response and Safety in Adults
with GHD
 Age: 18 to 65 years
 Estimated Enrolment: 136
 Study Design: Double-blind Parallel Group Randomised
Multiple Dose Study
 Study Start Date: June 2006
 Study Completion date: December 2007
 Study terminated: 10 December 2007
 Due to injection-site lipoatrophy
Source: NCT00308464: ClinicalTrials.gov

PFIZER INC.
 Nektar & Pfizer
 Jointly to develop an inhaled formulation of PEGylated
rhGH for growth disorders: Press release of November
2007
 No development reported in 2008
 Annual report, 2007 pipeline reports no active pipeline
for pegylated hGH
Nutropin Depot-
SR-rhGH by Genentech
Nutropin Depot: Encapsulated SR-GH
 Used ProLease, an injectable ER drug delivery system
developed by Alkermes
 Composed of microspheres formulated from a poly-D,L-
lactide-coglycolide matrix
 Approved by US FDA in 1999 for use in pediatric GHD
 Discontinued in 2004 by joint decision of Genentech &
Alkermes
 Available in 13.5 mg, 18 mg and 22.5 mg/vial
(somatropin, zinc acetate, zinc carbonate and PLG;
diluent: carboxymethyl cellulose sodium salt,
polysorbate 20, sodium chloride and SWFI, pH 5.8-7.2)
 Once a month 1.5 mg/kg body weight or 0.75 mg/kg
body weight twice a month
Nutropin Depot v. Nutropin AQ
A 32 wk, Phase II/III, randomized, parallel group,

multiple-dose, multicenter study

 135 adults enrolled with ADHD
 Target doses:
 0.3 mg/kg depot GH every 14 d or 0.006 mg/kg daily hGH
for men 35 yr old and older
 0.6 mg/kg depot every 14 d or 0.012 mg/kg daily GH for
all women and men less than 35 yr. Old
 Main Outcome Measure:
 Trunk adipose tissue measured by dual energy x-ray
absorptiometry
 Results
 % of fat decreased by 3.2 in GH depot and 2.5 in daily
GH whereas increased by 0.4 in the no treatment group
 Visceral adipose tissue area decreased by 9.1% in GH
depot group and by 6.8% in GH daily group
 Lean body mass and HDL increased in both treatment
groups
 Adverse effect profiles similar for both
 3 subjects receiving GH experienced serious episodes of
adrenal insufficiency
Hoffman et al., Efficacy of a Long-Acting Hormone (GH) preparation in patients with Adult GH deficiency, Study by
Veterans Affairs Palo Health Care System and Stanford University, Harvard Medical School, Oregon Heath Science
University, Genentech and Alkermes IN J.Clin. Endocrinol Metab 90: 6431-6440, 2005
 Adverse Events
 66% receiving depot GH and 50% receiving daily GH
 Edema: 24% receiving depot GH and 29% receiving
daily GH
 Arthralgias: 34% taking depot and in 31% taking daily
GH
 No intracranial hypertension, No significant changes in
mean fasting or 2-h postglucose challenge serum
glucose, insulin, or glycosylated hemoglobin levels
(0.2% increase in both groups)
 Adverse Events
 Fasting glucose levels more than 126 mg/dl at the end of
study in 2 subjects receiving daily and in one subject
receiving depot GH (postdose only)
 2 deaths in subjects receiving depot GH
 1 death due to motor vehicle accident
 2nd death as a result of adrenal crisis related to GH
 35 yr. Woman with panhypopituitarism who was taking replacement
hydrocortisone (10 mg bolus twice daily); developed gastroenteritis and
died at home 14d after first dose of GH depot
 Adverse Events
 12 serious adverse events in 10 subjects (4 receiving
depot and 6 receiving daily GH)
 3 serious including one fatal, 3 nonserious cases of adrenal
crisis or insufficiency diagnosed secondary adrenal
insufficiency and currently on glucocorticoid replacement
therapy
Nutropin Depot- FOI (US-FDA)
 Studies carried:
 An open-label PK study of hGH in adult patients with
GHD
 A phase I/II, multicenter, open-label study of the safety
and efficacy of rhGH administered monthly in children
with growth failure due to GH deficiency
 A phase III, multicenter, open-label study of the safety
and efficacy of rhGH administered in children with
growth failure due to GHD
 An open-label, long-term extension study of the safety
and efficacy of rhGH in children with growth failure due
to GHD
An Open-Label PK Study of hGH in
Adult Patients with GHD
 8 Males and 5 Females with a mean age of 47.5
years (range 27-67) and a mean weight of 87.4 Kg
(range 64.8-132.3)
 Pre-dose hGH mean level:0.2 ng/ml; IGF-I level: 64.4
ng/ml
 Administered single dose of 0.75 mg/kg somatotropin by
S.C.(weekly determination till Day 56)
 HGH peak mean level of 70 ng/ml after 12 hours post dose
 Median time for GH to return to baseline value-26.9 days
 IGF-I mean peak value of 463 ng/ml at 48 hours postdose
 Median time for IGF-I to return to baseline value-54.9 days
An Open-Label PK Study of hGH in
Adult Patients with GHD
 ADRs
 Overall no abnormal trends
 No detectable Abs to GH
 Most Frequent ADRs
 Injection site reactions (site erythema, itchiness, warmth,
swelling and pain)
 Peripheral edema
 Arthralgia & Headache
 Serious ADRs
 2/13 underwent Prolonged Hospitalization (Nausea &
vomiting)- related to drug
 One out of the two also experienced abdominal pain-related to drug
Phase I/II, Multicenter, Open-label
Study of rhGH for GHD in Children
 Initiated in November 1996 and completed in April
1998
 6 month study, 64 subjects enrolled at 12 medical
centres in US
 38 subjects with GHD & currently treated with daily
rhGH administered with 0.75 mg/kg every 4 weeks as SC
injection
 26 subjects with GHD & naive to rhGH treatment
 4 CT & 3 naive subjects received 0.75 mg/kg every 4
weeks (0.75q4)
 17 CT & 8 naive subjects received 1.5 mg/kg rhGH
every 4 weeks (1.5q4)
 11 CT & 9 naive subjects received 0.75 mg/kg rhGH
every 2 weeks (0.75q2)
 rhGH produces a
 positive growth response in naïve subjects with GHD at the
doses used, resulting in catch-up growth
 in subjects CT with daily rhGH, resulted in growth rates
appropriate for age and maintenance of standardised height
 No deaths
 1 serious ADR due to acute dehydration as a result of vomiting
and diarrhea with a viral gastroenteritis unrelated to rhGH
 7 subjects discontinued treatment
 2 CT subjects in 0.75q4 with history of hypoglycemia experienced
worsening of the condition
 1 subject suffered allergic reaction
 4 subjects associated with injection-site pain
 1 naïve subject in 0.75q4 group reported glycosuria at month 1
and hyperglycemia at month 2
 63 out of 64 reported events related to injection site
 7 reported severe, 4 discontinued
 21 subjects reported lipoatrophy
Phase III, Multicenter, Open-label
 Initiated in December 1997 and completed in
September 1998
 6 month study, 74 subjects enrolled at 27 medical
centres in US
 1.5 mg/kg administered once a month
 0.75 mg/kg administered twice a month
 Concluded as safe and effective therapy for
treatment of growth failure due to GHD
 ADRS
 No deaths, 4 serious adverse events unrelated to
treatment
 2 subjects discontinued
 One subject reported multiple events including buttock, groin
pain, dizziness, weakness, increased thirst, and nausea
 Second subject due to pain during injections
 Moderate Arthralgia in 3 subjects
 6 subjects reported allergic reactions
 ADRs
 Common Injection-site reactions in 50% patients: pain
during injection, nodules, erythema, bruising, and pain
postinjection; 28% subjects reported lipoatrophy
US-FDA Memorandum:Solomon Sobel,
Director Division of Metabolic &
Endocrine Drug Products
 Major issues
 Is Nutropin depot an acceptable alternative to daily
injection of GH?
 What population should be treated whether naïve or CT?
 What is the safety profile of Nutropin depot?
 Advantages cited:
 Dosing convenience
 Offers an alternate form if there are major issues of
compliance with a regimen of daily injections
 Pivotal studies not concurrently controlled with
daily injection regimens
 Lesser Efficacy
 In Naïve patients about 3 cm per year lesser response to depot
v daily injection
 Patients chronically treated with daily GH and shifted to depot
showed a 3.0 cm per year decline in growth rate
 Major safety issues- very frequent local reactions to injection
but no systemic safety issue
 Bone age advancement less
 Indirect indication of poorer efficacy
 No. of patients refused to continue on depot formulation due to
injection site reactions
 Each injection received patients experienced approx. 2.5-3 additional
symptoms of discomfort
 Lesser Efficacy
 PK/PD
 IGF-I returned to baseline days prior to the next dose suggesting that
patients receiving this product may not be properly treated in between
doses
 Conclusion
 Division recommends approval with labelling
stipulations in order to properly reflect the findings of the
studies
ADRs Reported for Various rhGH
Approved Brands
Name of Approved drug
Nutropin Depot Nutropin AQ Genotropin Accretropin Humatrope Saizen Omnitrope
n= 138 NCGS* 0-6 months n=60 n=86 Tev-Tropin
pediatric n=8018 n=573 n=52 N=32 6 mo n=164
patients 18 mo 18 mo 40 mo
AGHD PGHD
Overall 1.3% (103)
Injection site reactions 2 to 3 injection 0.3% (28) 50% 4.8% (8)
reactions/
injection
New onset or 0.2%(16) >3%
progression of
scoliosis
Gynecomastia 0.1% (12)
Any new onset or 0.1% (12)
recurring tumor
Arthralgia or arthritis 0.1% (10) 17.3% 17.3%(9) 23.3%(14)
Diabetes mellitus/ 0.1% (5) 10% 14%
glucose intolerance
Edema 0.1% (5) 10.8% 21.2%(11) 6.3%(2) 3.7%(2)
Cancer, neoplasm 0.0% (4)
Fracture 0.0% (4)
Intracranial 0.0% (4)
hypertension
Abnormal bone or 0.0% (3)
other growth
CNS tumor 0.0% (2)
New or recurrent 0.0% (2)
SCFE** or AVN***
Carpal tunnel 0.0% (1) 1.8%(1)
syndrome
*NCGS: National Cooperative Growth Study; ** : avascular necrosis; ***: slipped capital femoral epiphysis
Nutropin Depot Nutropin AQ Genotropin Accretropin Humatrope Saizen Omnitrope
n= 138 pediatric NCGS* 0-6 months n=60 n=86 Tev-
patients n=8018 n=573 n=52 n=32 6 mo Tropin
18 mo 18 mo
AGHD PGHD
Swelling, peripheral 17.5%
Upper respiratory 15.5% 13.5%(7) 3.6%(2)
infection
Pain, extremities 7% 14.7% 13.5%(7) 6.3%(2)
Paresthesia 10.8% 17.3%(9) 1.8%(1)
Headache 13% 9.6% >3% 7.7%(4) 9.4%(3) 14.5%(8) 7%
Stiffness of extremities 9.9%
Fatigue 7.9% >3%
Myalgia 4.9% 13.5%(7) 6.3%(2) 3.6%(2)
Back pain 2.8% 9.6%(5) 9.1%(5)
Nausea 8% >3% 3.6%(2)
Hypertension 7.7%(4)
Acne 5.8%(3)
Joint syndrome 5.8%(3)
Surgical procedure 5.8%(3)
Flu syndrome 7% 3.9%(2) 15.6%(5) 5.5%(3)
AST # 12.5%(4)
Asthenia 6.3%(2)
Cough increased 6.3%(2)
Rhinitis 6.3%(2) 3.6%(2)
ALT$ increased 6.3%(2)
Respiratory disorder 3.1%(1)
Hypesthesia 9.4%(3)
Pharyngitis 3.1%(1)
#: aspartate amino transferase; $: alanine amino transferase
Nutropin Nutropin Genotropin Accretropin Humatrope Saizen Omnitrope
Depot AQ 0-6 months n=60 n=86 Tev-
n=52 n=32
n= 138 NCGS* n=573 Tropin
pediatric n=8018 18 mo 18 mo 6 mo
patients AGHD PGHD
Hypothyroidism 16%
Eosinophilia 11%
Hematoma 9%
Hypertriglycerid 5%
emia
Leg pain 5%
Leukemia rare Rare
events
vomiting 5%
Genotropin ADRs
Safety Information from Pfizer:
Use of Genotropin
 Dose of diabetes medicines to be adjusted during
growth hormone treatment
 May increase the risk of a new tumor, particularly
certain benign brain tumors, in childhood cancer
survivors.
 higher in patients treated with cranial radiation.
Use of Genotropin
 May cause increased pressure in the brain.
 Lead to headaches and problems with vision.
 Treatment should be stopped and reassessed
 Patients with Turner syndrome, Prader-Willi syndrome, and
chronic renal insufficiency at higher risk of developing
increased pressure in the brain.
 Thyroid hormone replacement therapy should be
started or adjusted if needed.
Use of Genotropin
 Regular check-ups if they are receiving standard
hormone replacement therapy to treat a lack of more
than one hormone.
 In children experiencing rapid growth,
 curvature of the spine may develop or worsen called as
scoliosis.
 limping, or hip or knee pain may occur.
Active Pipeline for Long Acting hGH
BioPartners & LG Life Sciences
 LB03002- SR-hGH
 On track for EMEA submission in 2009
 Once-a-week sustained release formulation of rhGH
 Phase II/III study completed
 BioPartners:Licensee
 License to further develop and market in EU,AU,NL and
selected Asian & African countries
 Declage: SR-hGH-Launched in Korea for Adult GHD;
Approved by KFDA on March 09, 2007 & Launched in
March 2007
 Sales of Declage in 2007: KRW 3 billion (Approx. 12 crores
(INR))
 Basic Product Patent: US7276251 (Exp.: Dec.2019);
EP0918535 B1 (Exp.: Mar. 2018)
 Eutropin Plus for Paediatric GHD, NDA filed in Korea
Source: Press release from BioPartners, Baar, Switzerland (22.09.2008);

Annual Report: 2007 of LG Life Sciences, Korea
 LB03002- SR-hGH
 A SR drug composition consisting essentially of
microparticles of hyaluronic acid having a MW >
2,000,000 Da or an inorganic salt thereof (sodium,
potassium, lithium, calcium, ammonium, magnesium,
zinc, copper and cobalt salts of hyaluronic acid) and hGH
and stabilizer (polysaccharide, protein, amino acid, lipid,
fatty acid, inorganic salt, surfactant), a dispersant
(vegetable oil: corn, olive, soy bean, safflower,
cottonseed, sesame, coconut, castor) or preservative
encased in said microspheres with size ranging from 0.1
to 40 μm.
 SR formulation either in the form of S.C. Injection (once
a week) or an aerosol formulation administered nasally
or bronchi mucuous membrane
Source: US 7276251 B2
 SR-hGH for PGHD

 Solid microparticles using sodium hyaluronate and a
Niro spray drier; Characterized by Malvern particle size
analysis, SEM, SEC, RP-HPLC, SDS-PAGE
 PK & PD studies in beagle dogs; SR-hGH disersed in
medium-chain triglyceride at a dose of 1.0 mg hGH/Kg
S.C. (hGH:HA-1:1)
 Delayed absorption of hGH with Cmax of 69.5 ± 8.0 ng/ml and
Tmax between 10 and 12 hrs.
 Elevated IGF-I levels for 6 days with a maximum value higher
than the predose level by 350 ng/ml
 Physiochemical analysis with SEC, RP-HPLC, and SDS-PAGE
 Physiochemical analysis with SEC, RP-HPLC, and SDS-
PAGE
 No structural change in hGH as compared to native
 Monomeric content of hGH: 97.4%; purity:96%
 SR-hGH mean particle size: 5.6 ± 1.0 μm
 In vitro release: Complete release within 72 hr.
 No adverse effect during and after in vivo test using
beagle dogs
Source: Hahn SK, Kim SJ, Kim MJ & Kim DH, Biotech group,
LG Life Sciences, Korea in Pharm Res., 2004 Aug; 21(8):1374-81.
 SR-rhGH: Single administration through 26-guage

needle to cynomolgus monkey
 Prototype formulation with a ratio of hGH to HA as 1:3
 Pilot scale process developed under aseptic conditions
 Used for optimized formulation of SR-hGH for all preclinicals
and clinical findings
 Bioavailability comparable with hGH daily injection
formulation
 Toxicity studies: No adverse effects reported
Source: Hahn SK, Kim SJ, Kim MJ & Kim DH, Lee YP; Biotech group, LG Life Sciences, Korea in J
Control Release.,2005 May; 18; 104(2):323-35.
Phase II/IIIa -NCT00600808
 Assessor blinded, Randomised, Active-Controlled,
Multicentre, Parallel-Group Study of the Safety,
Efficacy and PK/PD of LB03002
 Administered weekly in children with growth failure due
to GH deficiency
 Evaluation of the safety, efficacy and PK/PD of
LB03002 in the treatment of GF in children with
GHD and to determine the dose for a subsequent
phase IIIb BPLG-004 study
 Age group: 4 to 10 years
 Study to be completed in May 2009
Phase II/IIIa - LB03002
 Randomised, comparator-controlled, assessor-
blinded, phase II study
 Assessed 37 (24 boys, 13 girls) pre-pubertal, GH-
naive children with GHD in 11 European countries
for PK/PD at doses of 0.2,0.5 or 0.7 mg/kg
 GH, IGF-I and IGFBP-3 concentration monitored
 Once a week administration of LB03002 for 13
weeks
Peter F, et al., PK and PD profile of a new sustained-release GH formulation, LB03002, in

children with GH deficiency: Eur J Endocrinol. 2008 Dec.12 (Epub ahead of print)
Phase II/IIIa - LB03002
 4 fold increase in GH Cmax
 Increase in IGF-I and IGFBP-3 Cmax values
 Adequate stimulation of IGF-I & IGFBP-3
Peter F, et al., PK and PD profile of a new sustained-release GH formulation, LB03002, in

children with GH deficiency: Eur J Endocrinol. 2008 Dec.12 (Epub ahead of print)
SR-hGH Phase II Completed in Europe
 Trial, a part of a joint study initiated by American
and European pediatric endocrinology societies
 50 stunted children received treatment at 6 European
countries for one year in 2005
 US FDA approval expected in 2008- Prediction
LG Life Sciences: Annual Report-2006

Novo Nordisk
 NNC126-0083: Pegylated rhGH
 Highest Phase: Phase II
 Site specific modification and PEGylation of rhGH using
transglutaminase
 Catalyzes acyl transfer reactions between the gamma-
carboxamide groups of protein-bound glutamine (Gln)
residues, which serves as acyl donors, and primary amines
resulting in the formation of glutamic acid and ammonia
 Uses the amino-derivative of PEG as substrate for enzymatic
reaction with Tgase
 Covalently binds PEG polymer
Novo Nordisk
 NNC126-0083: Pegylated rhGH
 NCT00715689: Dose Study investigating Safety,
Tolerability, PK and PD in GHDA
 Age group: 20 to 65 years
 Enrolment:32 (Currently recruiting patients)
 Start date: July 2008; Completion date: March 2009
Source: clinicaltrials.gov
Ambrx: Reconstituting Chemically
Orthogonal Directed Engineering
(ReCODETM Technology)
 Specialialized orthogonal tRNA synthetases evolved
to selectively and specifically amino-acylate a
similarly orthogonal suppressing tRNA (tRNAA 0)
with unique, chemically specified amino acids
 Cell's transcriptional apparatus then incorporates the
Ambrx aa elongating peptide sequence at positions
designated by the amber codon while in absence
elongation gets terminated at Amber
 AA are designed to include side chains that are
chemically reactive using coupling chemistry
preserving protein function & does not react with
Ambrx: Reconstituting Chemically
Orthogonal Directed Engineering
(ReCODETM Technology)
 tRNA0 and tRNA0 synthetases are orthogonal
 Do not interact with endogenous tRNA and tRNA
synthetases
 Valid technology for E.coli, yeast and mammalian
cell systems with the lead in E.coli expressed
proteins
The components of this reconstituted system are represented in the diagram and include the unique amino acid (1),
the tRNAo to which it is conjugated by (2) the tRNA synthetase (RSo) to create an amino-acyl tRNA that recognizes
(suppresses) (3) the stop codon TAG (amber) (4) placed at any position in the protein of interest’s coding sequence.
Ambrx: Patent Portfolio
 WO2008077079  WO2007056448
(FD: Dec. 2007) (FD:Nov.2006)
 WO2008030614  WO2007021297
(FD: Sep. 2007) (FD: Dec. 2005)
 WO2008030612  WO2006132969
(FD: Sep.2007) (FD: June 2006)
 WO2007094916  WO2006073846
(FD: Jan. 2007) (FD:Dec. 2005)
Ambrx: Patent Portfolio
 WO2007079130  WO2006071840
(FD: Dec. 2006) (FD:Dec. 2005)
 WO2007070659  WO2006069220
(FD: Dec. 2006) (FD: Dec.2005)
 WO2007059312  WO2005074650
(FD: Nov. 2006) (FD: Jan.2005)
Ambrx Incorporation- ARX201:
Long acting hGH analogue
 Phase I/II clinical trial data for ARX201
 Developing Partner: Merck Serono
 Once a week S.C. Injection administered for 26 weeks
 22 AGHD patients,who have not received hGH
replacement therapy in past 6 months
 IGF-I levels increased to normal values
 Mean truncal fat loss of 5.6% and a mean total body fat
loss of 1.3%, mean increase in lean body mass of 3.6%
 Well tolerated with temporary pain at the injection site
 No neutralising Abs to PEGylated hGH or to native hGH
Press Release from Ambrx Inc., 13/11/2008
Ambrx: ARX201
 Phase IIb study to evaluate the safety, tolerability,
PK and PD profile of ARX201 following repeated
dosing to young adult patients with chilhood onset
GHD
 Recruiting patients: Start date: July 2008, Expected
Completion: January 2010, Age group: 18 to 30 years
ClinicalTrials. gov identifier: NCT00778518

Asterion Limited, Sheffield, UK
 ProFuseTM technology
 A ligand-receptor fusion of growth hormone forms a
dimer and is a potent long-acting agonist
 GHR-GH-GHR complex formed by GH interacting through
site 1 and site 2 with GHR
 Mutations in site 1 of GH increases affinity of GH for its
binding domain on GHR and such modified GH act as agonists
 Uses a chimeric polypeptide consisting of modified site 1 GH
linked to ligand binding domain of GH receptor
Wilkinson et al., University of Sheffield,UK in Nature Medicine 13,1108-1113 (2007)

 ProFuseTM technology pipeline
 Partnered: Third-generation Growth Hormone Agonists
and Antagonists
 Development Partner: Ipsen Pharma
 Target: GHD in Adults; Stage: Preclinical
 Third-generation GH agonist: Potential treatment for growth
disorders [$2.5Bn]
 Third-generation GH antagonist: Potential treatment for
acromegaly [$1Bn]
 Advantageous over pegylation and depot technologies
 Thermally stable and should not require complex cold chain
distribution
 Safety and tolerability, conserved & enhanced potency
 Improved PK/PD properties
 Reduced clearance and prolonged biological action while
retaining the specificity and use of native proteins
 PCT applications:
 WO2003070765 (FD: Dec.2002)
 US2005123558/EP1456385 A2
 WO2008032059 (FD:Sep.2007)
 Internal Development: Third-generation AFT™
Products
 AFT™ -EPO: Potential treatment to maintain the red blood cell
population and prevent anaemia [$12 Bn]
 AFT™ -GCSF: Potential treatment for neutropenia (a
deficiency in white blood cells associated with
myelosuppressive chemotherapy) [$4.4Bn]
 Unpartnered products: Third-generation AFT™ –
Products
 AFT™ -Interferon alpha: Hepatitis B&C [$2.5Bn]
 AFT™ -Interferon beta: Multiple sclerosis [$4.4Bn]
 Unpartnered products: Third-generation AFT™ –
Products..........
 AFT™ -Leptin: Potential treatment for conditions associated
with malnutrition (immune deficiency, TB, secondary
amenorrhoea, infertility)
 AFT™ -Prolactin: Potential treatment for stem cell
proliferation or certain cancers
 AFT™ IGF-1: Potential treatment for growth hormone
deficiency or type II diabetes
 AFT™ -IL-2: Potential treatment for advanced renal cell
cancer and malignant melanoma.
Aegis Therapeutics LLC,USA
 ProTekR technology
 RT Stable hGH formulation suitable for Metered Nasal
Spray Delivery
 Covered by US7425542 B2 (Exp.: June 2026)
 Lyophilized formulation consisting of:
 HGH,
 buffering agent,
 alkylglycoside selected from group consisting of dodecyl maltoside,
tridecyl maltoside, sucrose mono-dodecanoate, sucrose mono-
tridecanoate, and sucrose mono-tetradecanoate;
 mucosal delivery enhancing agent,
 benzalkonium chloride or chloroethanol,
 a membrane penetration enhancing agent,
 a modulatory agent of epithelial junction physiology,
 Use of patented nontoxic alkylsaccharides
excipients
 Increases transmucosal absorption of proteins and
peptides upto 30 kda MW;
 Stabilizes proteins and peptides against aggregation
 Maintain physical stability and physiological activity
 Composed of simple sugar (maltose or sucrose) coupled
to long chain fatty acids or long chain alcohols that
metabolize to CO2 and water and regarded as GRAS
Maggio Edward: Novel Excipients prevent aggregation in manufacturing and formulation

of protein and peptide therapeutics, BioProcess International, November 2008
 Use of patented nontoxic alkylsaccharides
excipients
 Water soluble and hence can be formulated in stable
aqueous or lyophilized forms
 Compatibility with all routes of administrations
 ProTek excipient increased the stability of hGH in
20 day study
 ProTek type A Excipients
 Long chain alkyl polyglucosides
Absorption Enhancement Effect of
ProTek type A Excipient on Intranasal
Absorption of Human Insulin

hGH Stability: 20 Day Study

Safety and Toxicity Data for ProTek
type A Alkylsaccharide
Maggio Edward: Novel Excipients prevent aggregation in manufacturing and formulation of protein
and peptide therapeutics, BioProcess International, November 2008
Modigene Inc.,Israel
 hGH-CTP: Long acting hGH: MOD-401
 Uses a short amino acid sequence, the carboxy terminal
peptide (CTP) which is attached to hGH
 Obtains exclusive license from Washington University
 Platform validated in FSH-CTP by Schering-Plough
which completed Phase III
 Xcellerex Inc.,: GMP grade manufacturer for hGH-CTP
for preclinical and Phase-I trials
 Stage:Preclinicals completed
 Once weekly administration
 Receives $10 million from Israeli Office of Chief
Altus Pharmaceuticals, USA
 ALTU 238-Long acting crystal formulation of hGH
 Uses proprietary CrystalomicsTM
 Treatment of GHD in both adults and pediatric
population
 Highest phase- Phase II completed in June 2006
 A multicentre, randomised phase II study in 13 adult patients
with GHD in US
 Administered 3 weekly S.C. Injections of 5.6 or 11.2mg
through fine 30-guage needle
 Most frequent Adverse event was mild injection site reaction
 Agreement with Althea technologies for phase III studies
to commence in last quarter of 2008 Press releases: Altus pharmaceuticals
Altus Pharmaceuticals, USA
 Long Acting Crystal Formulation of hGH
 Crystals of rhGH coated with a monomolecular layer of
positively charged polyarginine
 PD & PK determined in hypophysectomized rats and
monkeys injected S.C. Once a week
 Standard weight gain assay in rats and serum IGF level
in monkeys as end points
 Formulation as non-viscous suspension
 Easy administration through fine 30-guage needle
 Targeting improved patient convenience and compliance
Govardhan et al., Pharm. Res. 2005 Sep; 22(9)

Bolder Biotechnology Inc.,USA
 Pegylated rhGH: BBT 031 using site specific
pegylation
 Highest Phase: Phase I
 Mono-pegylated GH by substituting cysteine for
threonine 3 (T3C) and conjugating 20 kda PEG through
thiol group of substituted cysteine
 10 to 20 fold longer circulating half life than GH
 In December 2008 awarded $US 1.9 million phase II
Small Business Innovation Research (SBIR) grant from
the NIAID & NIH
Press releases from Bolder Biotechnology

 Targets treatment of
 GHD,
 short stature in children and
 HIV associated adipose redistribution syndrome (HARS)
 Subset of abnormal disorders of fat distribution and modified
metabolism often called HIV-related lipodystrophy syndrome
 Patent Portfolio:
 US7399839 (Exp.:Aug.2020)
 US6753165 (Exp.:Jan.2020)
 US7153943 (Exp.:Jan.2020)
 US6608183 (Exp.: Jan.2020)
 POC in Hypophysectomized (HYPOX) male
Sprague Dawley Rats
 9 day study by administering PEG-T3C by S.C. &
I.V.Route
 Terminal half life (IV & SC route)
 GH - 0.34h; PEG-T3C hGH-10h (measured 0.25-4h & 10 to 72h after
injection resp.)
 GH - 0.34h; PEG-T3C hGH-9h (measured 0.25-4h & 10 to 72h after
injection resp.)
 Serum levels of proteins measured by ELISA
 Data reported as ± SD for three rats/group
 Rats dosed at 100 mcg protein/kg
Cox et al., Long-Acting, Mono-PEGylated Human GH; Endocrinology, April 2007,
148 (4):1590-1597
PK properties of rhGH (Nutropin) and
PEG-T3C after a single i.v. (A)
& s.c.(B)
Cox et al., Long-Acting, Mono-PEGylated Human GH; Endocrinology, April 2007,

148 (4):1590-1597
Novartis AG
 Oral rhGH
 Uses proprietary Eligen technology from Emisphere
 Emisphere initially partnered with Lilly but in 2004
initiated new partnership with Novartis
 Novartis has worldwide exclusive development and
marketing rights
 No clinical development reported
PharmaEssentia Corporation, Taiwan
 CEO from Biogen, USA
 PEG rhGH: In Lead Development
 Phase I targeted in Q1 of 2010
 Uses 20 kda m-PEG aldehyde derivative as RM
from SunBio Inc., USA
 PCT applications: WO2007079404 (FD: Dec.2006)
WO2009006579 (FD
July 2008)
Press releases from PharmaEssentia Corporation

PharmaEssentia Corporation, Taiwan
 IND submission for PEG-IFNalpha 2b- P1101
 Claims a single form compared to 8 isomers of Pegintron
and 14 isomers of Pegasys
 Less frequent administration regime of every two weeks
or more as against once a week administration for
Pegintron
Press releases from PharmaEssentia

Corporation
Critical Pharmaceuticals, UK
 SR formulations of rhGH for GHD
 Two candidates
 CP 016: biweekly injection
 Completed Preclinical in UK
 CP 024: once daily nasal spray
 Currently in discovery research
 Uses CriticalMixTM delivery technology based on
supercritical fluids
Media releases from Critical Pharmaceuticals

Critical Pharmaceuticals, UK:
Uses CriticalMix technology
TM
 CO2 on reaching the critical temperature (Tc of -31.04°C, of

a material is the temperature above which distinct liquid and gas
phases do not exist but exist only as one phase. Above the Tc,
liquid cannot be formed but on application of pressure solid can be
formed) and critical pressure(7.377 MPa) (vapor pressure at T c)
becomes supercritical (scCO2) and shows dual gas & liquid
properties
 By using scCO2, PLGA (poly(lactide-co-glycolide)) & PLA
(poly(lactic acid)) are liquefied at near ambient temperatures and
rhGH mixed into the polymer
 On release of pressure, the polymers solidify around the substance,
encapsulating it homogeneously dispersed throughout the matrix
 Allows encapsulation of thermally liable or solvent sensitive drugs
without issues of drug stability
Phage Biotechnology, USA
 Platform for soluble expression of proteins in
prokaryotic platform
 Cloning of protein coding gene in bacterial plasmid
 Bacteria infected with bacteriophage resulting in
supersynthesis of the desired human product followed by
lysis liberating the protein in completely soluble and
active form
 rhGH (Syntropin)
 Partnered with BioPolymed Inc., a Korean firm for
pegylation platform
Phage Biotechnology, USA
 US6268178  US7252818
 (Exp.:May 2019)  Exp.:Aug.2023
 US6794162  US7344876
 (Exp.: May 2021)  Exp.:Jan.2024
 US6773899  Appln. No.11/187522
 (Exp.: Aug.2021)  (FD:Dec.2005)
 US6642026  hGH conjugated with
biocompatible polymer
 (Exp.:Aug.2021)
Biological activity of Phage hGH and
PEG-hGH in cell based asssay
Flamel Technologies, USA
 Medussa Platform
 HGH-XL: Long acting hGH in preclinicals
 Flamel's Medusa® polymer is made of glutamic acid, a
naturally occurring aminoacid, and Vitamin E.
 Polymer is amphiphilic and spontaneously forms stable
nanoparticles in water.
 Consists of hydrophobic nanodomains rich in Vitamin E
and hydrophilic polyglutamate that are exposed to water.
 Robust over a wide range of pH values and can be stored
as either stable liquid or stable dry forms that can be
easily reconstituted in water.

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Evaluation of PEG-

Source: Newport Horizon Premium (IMS Database)

Source: Annual reports:2007

Growth Hormone Deficiency in Children: In Endocrinology (Fifth Edition) Vol.1,pp:747,

Source: NCT00314938: ClinicalTrials.gov

Source: NCT00308464: ClinicalTrials.gov

multiple-dose, multicenter study

Source: Press release from BioPartners, Baar, Switzerland (22.09.2008);

 SR-hGH for PGHD

 SR-rhGH: Single administration through 26-guage

Peter F, et al., PK and PD profile of a new sustained-release GH formulation, LB03002, in

Peter F, et al., PK and PD profile of a new sustained-release GH formulation, LB03002, in

LG Life Sciences: Annual Report-2006

ClinicalTrials. gov identifier: NCT00778518

Wilkinson et al., University of Sheffield,UK in Nature Medicine 13,1108-1113 (2007)

Maggio Edward: Novel Excipients prevent aggregation in manufacturing and formulation

Maggio Edward: Novel Excipients prevent aggregation in manufacturing and formulation

Maggio Edward: Novel Excipients prevent aggregation in manufacturing and formulation

Govardhan et al., Pharm. Res. 2005 Sep; 22(9)

Press releases from Bolder Biotechnology

Cox et al., Long-Acting, Mono-PEGylated Human GH; Endocrinology, April 2007,

Press releases from PharmaEssentia Corporation

Press releases from PharmaEssentia

Media releases from Critical Pharmaceuticals

 CO2 on reaching the critical temperature (Tc of -31.04°C, of

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