Statement from the Growth Hormone Research Society

Keswick HallCharlottesville, Virginia

May 7 - 10, 2000

Keswick Safety Presentation-final2.ppt6-19-00

Critical Evaluation of the Safety of Recombinant Human Growth

Hormone Administration• Background• Epidemiological and experimental data used

to assess relationships of GH, IGF-I and cancer risk

• Safety aspects– GH therapy in children– GH replacement in adults– Pharmacological GH treatment in adults

• Closing remarks

ParticipantsRobert Baxter

Bengt Åke Bengtsson

Sandra L. Blethen

Werner F. Blum

Bjorn Carlsson

Lena Carlsson

Paul V. Carroll

Jens Sandahl Christiansen

Peter E. Clayton

David R. Clemmons

Pinchas Cohen

Christopher T. Cowell

Gordon B. Cutler

Judith E. Fradkin

Joseph M. Gertner

Sue Hankinson

Raymond Hintz

Jörgen Isgaard

Gudmundur Johannsson

Jens Otto Lunde Jørgensen

Anne-Marie Kappelgaard

Irene Langbakke

Derek LeRoith

Barbara Lippe

Saul N. Malozowski

Thomas Maneatis

John P. Monson

Yoshikazu Nishi

Michael N. Pollak

Iain Robinson

Ron Rosenfeld

Daniel E. Salazar

Akira Shimatsu

Peter H. Sönksen

Peter Stein

Christian J. Strasburger

Elisabeth Svanberg

Anthony Swerdlow

Katsuhiko Tachibana

Hiroaki Takahashi

Jukka Takala

Toshiaki Tanaka

Michael O. Thorner

Greet van den Berghe

A.J. van der Lely

Patrick Wilton

Douglas Yee

Background• Lessons learned since recombinant human

GH was introduced to the market in 1985 • Unprecedented level of scrutiny has lasted

more than 15 years because – Jacob Creutzfeld disease relationship to

pituitary-derived GH– Potential association between GH and

leukemia– GH was the second recombinant protein

brought to market

Epidemiological and

experimental data used to

assess relationships of GH,

IGF-I and cancer risk

Epidemiological Data

Active acromegaly, a disease characterized

by raised serum GH, IGF-I, and IGFBP-3

levels has been reported to be associated

with

• increased incidence of colonic neoplasia,

although conflicting data exist

• no increased incidence of breast or

prostate cancers

Recent epidemiological surveys, including case-control, as well as follow-up designs report

• Serum IGF-I levels in upper normal range may be associated with increased risk of developing prostate cancer and breast cancer in premenopausal, but not postmenopausal women

• High IGF-I and low IGFBP-3 levels in serum may be associated with increased risk of these two tumors, as well as risk of colon cancer

• High serum IGFBP-3 levels alone have also been related to reduced cancer risk

Epidemiological Data

Consensus regarding background information

• A cause-effect relationship between serum

IGF-I and development of cancer has not

been demonstrated

• Serum IGF-I levels may be affected by

additional factors other than GH status,

including nutrition

Epidemiological Data

Studies in vitro and in animal models

• Most cells, including cancer cells, possess IGF-I receptors and respond to IGF-I with increased growth

• IGF binding proteins (IGFBP) and IGFBP proteases also modulate cell growth, and over expression of IGF-I receptors induces tumor formation in animal models

• No evidence that systemic administration of IGF-I to animals stimulates tumor formation, although it can increase growth of some established tumors

Experimental Data

Studies in vitro and in animal models

No studies have evaluated direct (IGF-independent)

effects of GH on tumor formation

• In GH transgenic animals, specific activation of

GH receptors with concomitant elevations in

circulating IGF-I did not result in breast, colon or

prostate tumor formation

Experimental Data

• No data to suggest that IGF-I and IGFBP-3 modulate cancer risk in GH-treated patients

• Patients with previous malignancies or history of radiation therapy carry significant risk for recurrence and second malignancy

• Recommend measurement of serum IGF-I levels in patients receiving GH treatment; place of regular IGFBP-3 monitoring is not defined

• Recommend that IGF-I level be maintained within appropriate age- and gender-related normal range in GH-deficient adults during long-term therapy

Epidemiological DataGH Replacement and Cancer Risk

• Current labeling for GH states that active

malignancy is a contraindication for GH

treatment. There are, however, no data to

support this labeling.

• Current knowledge does not warrant

additional warning about cancer risk in the

product label.

Epidemiological DataRegulatory Aspects

Safety - GH Therapy in Children

Recombinant human GH has been used in an estimated 50,000 children.

• Significant adverse drug reactions rare

• Large international databases have been useful in quantifying adverse events, and hence, addressing safety issues

• Extended follow-up into adulthood of children who have discontinued GH treatment would be ideal - this may only be achievable in subset of patients

Children receiving GH, who have had a malignancy, account for approximately 20% of patients enrolled in international databases.

• Existing evidence does not indicate that GH treatment will increase tumor recurrence in those successfully treated for their primary lesion

• In patients who have been rendered GH deficient by tumor and/or its treatment, timing of initiation of GH treatment must be decided on basis of individual case, once tumor treatment is completed and condition is in remission

Safety - GH Therapy in ChildrenMalignancy Risk

All subjects who have had a malignancy and received

treatment for it are at risk for a second malignancy.

• No evidence that GH treatment increases risk of this

process based on limited data available

• No evidence that de-novo cancer and leukemia are

increased in GH recipients

• In view of continuing evolution of oncology

treatments, ongoing surveillance of GH recipients

with appropriate age-related controls is important

Safety - GH Therapy in ChildrenMalignancy Risk

Certain patient groups who receive GH treatment carry an intrinsic risk of developing malignancies, including those with Neurofibromatosis type 1, Fanconi anemia, Downs and Bloom syndromes.

• Although no evidence that GH replacement poses increased cancer risk, we recommend that such children be carefully monitored with regard to tumor formation

Safety - GH Therapy in ChildrenMalignancy Risk

• Has been reported in 1/1000 children receiving GH treatment; may be underestimate

• Headache in children on GH treatment should be carefully evaluated

• Fundoscopic examination should be performed before initiation of GH treatment and repeated when clinically indicated

Safety - GH Therapy in ChildrenBenign Intracranial Hypertension

• Reduction of insulin sensitivity is physiologic effect of

GH, however, glucose homeostasis is maintained in

vast majority of patients

• Most available surveillance data do not demonstrate

increased incidence of diabetes, either type 1 or type

2, associated with GH treatment

• There are, however, subgroups of patients inherently

at risk of developing diabetes - these should be

carefully monitored

Safety - GH Therapy in ChildrenGlucose Metabolism

• Diabetes mellitus is not contraindication

to GH treatment in children

• Diabetic care should follow standard

clinical practice

Safety - GH Therapy in ChildrenGlucose Metabolism

• Some underlying disorders that are treated

with GH therapy can be associated with

slipped capital femoral epiphysis, scoliosis

and avascular necrosis

• No evidence these conditions are caused

by GH treatment; however, scoliosis may

be exacerbated when growth is accelerated

Safety - GH Therapy in ChildrenSkeletal Disorders

• No compelling evidence that GH treatment

has any adverse effect on pubertal

development and gonadal function

• GH can affect metabolism of thyroid

hormones and cortisol

Safety - GH Therapy in ChildrenInteraction with Other Hormones

• No data to support discontinuation of GH

replacement treatment during illness

• Risk of hypoglycemia should be considered

in children with GH deficiency who

discontinue GH treatment

Safety - GH Therapy in ChildrenGH Treatment and Intercurrent Illness

Issues related to GH treatment in patients with non-GH deficient disorders

• Monitoring glucose homeostasis in Turner syndrome and glucose homeostasis and lipid profiles in chronic renal failure should be undertaken at intervals determined by standard clinical practice

• In patients with chronic renal failure treated with GH who receive renal transplant, assessment of graft function and surveillance for development of malignancy should be carried out according to routine nephrology guidelines

Safety - GH Therapy in Children

• Prevalence of diabetes mellitus (DM) increased in hypopituitary adults

• Metabolic actions of GH include insulin antagonism• THUS, recommend that glucose metabolism be

assessed in all patients before and during GH replacement

• DM (or impaired glucose tolerance) not a contraindication to GH replacement; care of diabetes in GH-replaced adults should follow standard guidelines, but intensified monitoring of metabolic control is advocated in early phase of GH replacement of such patients

Safety - GH Replacement in AdultsGlucose Metabolism

• Eye examination is indicated in case of overt diabetes

and should be conducted in accordance with

standard guidelines

• Stable background retinopathy should not lead to

discontinuation of GH replacement

• Development of pre-proliferative changes and

presence of proliferative retinopathy are

contraindications to GH replacement

Safety - GH Replacement in AdultsGlucose Metabolism

• Symptoms related to fluid retention may be

encountered especially in early phase of GH

replacement

• This partly reflects a GH-induced, dose-dependent

normalization of tissue hydration

• Monitoring of hydration during GH replacement

should include body weight measurement, patient

interview and clinical examination

Safety - GH Replacement in AdultsFluid Retention

• In the case of persistent symptoms

attributable to fluid retention, reduction of GH

dose should be considered

• Increased awareness of such symptoms and

signs are recommended in patients with

congestive heart failure

Safety - GH Replacement in AdultsFluid Retention

• Growth hormone increases extrathyroidal

conversion of T4 to T3 - thyroid function

should be monitored in all patients

• GH may decrease serum total cortisol

concentrations by decreasing circulating

cortisol binding globulin

Safety - GH Replacement in AdultsInteraction with Other Hormones

• Even though clinical implications for these

observations are uncertain, increased

awareness of glucocorticoid status is

recommended in all patients

• Possibility that overt ACTH insufficiency may

be unmasked during GH replacement (as a

result of inhibition of 11bHSD1) should be

considered

Safety - GH Replacement in AdultsInteraction with Other Hormones

• Increased prevalence of cardiovascular

disease in active acromegaly cannot be

extrapolated to GH-replaced hypopituitary

adult

• Monitoring of cardiovascular function

should follow standard of care for normal

population

Safety - GH Replacement in AdultsHeart Function and Lipoproteins

GH replacement in adults is known to increase serum levels of lipoprotein(a).

• Clinical implications - if any - are uncertain and should be weighed against beneficial effects of GH replacement on other cardiovascular risk factors

• Measurement of lipoprotein(a) not recommended as standard procedure in hypopituitary patients

Safety - GH Replacement in AdultsHeart Function and Lipoproteins

• Increased incidence of certain malignancies

has been reported in hypopituitary adults,

but no evidence that it is associated with GH

replacement

• Current recommendations for cancer

prevention and early detection in general

population should be implemented in GH-

treated hypopituitary adult

Safety - GH Replacement in AdultsCancer risk and Tumor Recurrence

• To date no evidence to suspect that GH replacement influences recurrence rate or regrowth of pituitary/peripituitary neoplasms

• Standard clinical practice requires regular pituitary imaging in patients with history of pituitary pathology

• Baseline imaging study recommended in all patients before instituting GH replacement therapy

Safety - GH Replacement in AdultsCancer Risk and Tumor Recurrence

Safety - PharmacologicalGH Treatment in AdultsICU Trials

• Power of placebo-controlled trials has been demonstrated with intensive care unit (ICU) studies, which showed that mortality was doubled in severely ill patients treated with high doses of GH

• These studies have refuted clinical practice beliefs that high-dose GH is beneficial in this situation

ICU Trials

• Two placebo-controlled clinical trials (522 ICU

patients) demonstrated that mortality increased

from 19% (placebo-treated) to 42% (GH-treated)

• Prolonged stay ICU patients following

complications from open heart or abdominal

surgery, multiple accidental trauma or those with

acute respiratory failure were included

Safety - PharmacologicalGH Treatment in Adults

ICU Trials

• Supraphysiological doses of GH (5.3-8 mg or

0.07-0.13mg/kg per day) were administered

• Most common causes of death were multi-organ

failure, septic shock and uncontrolled infections

• Baseline patient characteristics, severity of illness

and diagnostic category did not explain increased

mortality

Safety - PharmacologicalGH Treatment in Adults

• Any GH treatment, other than replacement in those who have GH deficiency, should be considered as pharmacological

• In specific conditions where pharmacological GH treatment is being considered, standard safety data should be collected and protocols for new drug development should be followed

• Detrimental outcome of high dose GH treatment in ICU patients cannot be extrapolated to other conditions, which may potentially benefit from GH treatment

Safety - PharmacologicalGH Treatment in Adults

• At present, not recommended that pharmacological GH treatment be initiated in adult ICU patients

• In patients receiving pharmacological (in contrast to replacement) GH treatment, cessation of GH treatment should be considered when patient is critically ill

• ICU trials should not discourage new studies of GH treatment in groups who may benefit from GH

• Pharmacological doses used in such trials should be minimum effective dose for relevant endpoint

Safety - PharmacologicalGH Treatment in Adults

GH levels and critical illness

• GH-IGF system is dysregulated in critical illness

• Not known whether this has effect on outcome in

such patients, nor whether GH-deficient adults,

including those receiving replacement therapy, are at

higher risk for adverse outcomes when critically ill

Safety - PharmacologicalGH Treatment in Adults

GH levels and critical illness

• GH deficiency in adults and children, however, is frequently part of a more extensive pituitary deficiency including adrenocortical deficiency, which should be considered during critical illness in such patients

• No data to support discontinuation of appropriate GH replacement in patients receiving intensive care treatment for critical illness, or during period of less severe illness or in relation to surgery

Safety - PharmacologicalGH Treatment in Adults

• Extensive data collected on large numbers of children and adults treated with GH indicate that, for current approved indications, GH is safe

• Nevertheless, this workshop highlighted a number of areas where ongoing surveillance of long-term safety of GH replacement is important (cancer – glucose homeostasis – high dose pharmacological GH treatment)

– Appropriately designed follow-up studies using adequate epidemiological tools and untreated controls are required

Closing Remarks