Download Therapies In PWS

Therapies In PWS
Jennifer Miller, MD
Pediatric Endocrinology
University of Florida
Agenda
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Growth hormone treatment
Provigil
N-acetylcysteine
New research into hyperphagia treatments
Growth Hormone Treatment
• GH treatment has benefits at any age on body
composition, metabolism, cognitive function
GH deficiency – effects on brain and
cognition
• Compared with controls, children with isolated GH
deficiency (mean age 8.8 yrs) had lower Full-Scale IQ,
Verbal Comprehension, Processing Speed, and
Movement-Assessment Battery for Children.
• Verbal Comprehension Index scores correlated
significantly with insulin-like growth factor-1 and
insulin-like growth factor binding protein-3 standard
deviation scores in isolated GH deficiency.
• Children with isolated GH deficiency had smaller
splenium of the corpus callosum, left globus
pallidum, thalamus and hippocampus .
Growth Hormone for infants with
PWS
• Data suggests that GH deficiency that is untreated
prior to childhood may result in abnormalities in
brain structure and cognition.
• Standard recommended starting dose is 1
mg/m2/day.
• On standard starting dose of 1 mg/2/day fat mass
declines initially, but then increases after 2 yrs of
treatment. Whereas on a higher dose of 1.5
mg/m2/day the fat mass continues to decline over
time, indicating that higher doses may be more
beneficial for infants over time.
GH in infants
• GH treated infants had improved mental and
motor development compared to controls.
• Those with lowest motor development have the
most profound improvement on GH.
• Hand and foot length never completely
normalize compared to NL population, whereas
arm span and tibia length completely normalize
Why is it beneficial for infants to start GH
treatment despite adequate growth?
• GH decreases ghrelin (hunger hormone) which is high
even in infants with PWS, so may alter the natural course
of the appetite progression in PWS.
• Data in PWS mice shows hypoglycemia and deficits in
insulin secretion in infancy – GH increases insulin and
glucose levels, which may be why it is beneficial for
infants in terms of cognitive development.
• GH treatment shortens the initial failure-to-thrive phase
of PWS
• May impact brain development as well as
cognition.
Other Benefits
• Data from Carrel et al and Hokken-Koelega
et al, shows that GH treatment for infants
improves IQ and psychomotor
development.
• We found that individuals treated with GH
before age 1 had decreased fat mass, lower
BMI, and higher resting energy expenditure
as they age, compared to those treated
after age 1, indicating that early treatment
with GH may help prevent or ameliorate
the obesity associated with PWS.
GH Effects on Cognition
• GH treatment significantly improves abstract
reasoning and visuospacial skills in children.
• With no treatment there is a decline in of
certain cognitive skills in adolescence with
PWS, but GH treatment prevents that decline.
GH in Adults with PWS
• GH treatment improves muscle mass and
decreases body fat in adults with PWS.
• Most common side effect of adult treatment was
edema.
• Insulin and glucose levels increased during
treatment, but no increased incidence of
diabetes.
• Few patients had headache and myalgia.
• Contraindications to GH therapy in adults with
PWS are morbid obesity, severe untreated
obstructive sleep apnea.
5 years of adult GH therapy
All patients had a
mild increase in
insulin resistance on
GH.
2 developed glucose
intolerance on GH
1 patient developed
Type 2 diabetes (was
in the non-GH
treated group).
Cognitive Effects – Adult GH
• Improvement in mental speed and flexibility and
motor performance
• When GH stopped parents documented impairment
in physical and social status as well as overall
functioning
• Parents reported improvement in self-control and
both parents and patients reported increased vitality
on GH. Patients reported improvement in overall
quality of life.
Monitoring IGF-1 levels
• IGF-1 is a surrogate marker for GH.
• IGF-1 increases significantly over years of treatment
and is above the normal range in the great majority of
individuals with PWS after 2 years of treatment.
• Reducing GH dose causes increases in body fat and
decreases in muscle mass, so it is suggested to reduce
the dose only if the IGF-1 levels are >2 standard
deviations above the mean.
• We recommend monitoring IGF-1 levels every 3-6
months in infants and children and every 6-12 months
in adults.
GH and sudden death
• In 2003 a series of deaths on children who had recently
started GH treatment was reported.
• Several other reports of sudden death occurring in sleep
within 1-3 months after starting GH treatment followed this
initial report – the majority of individuals were obese males.
• Martin Ritzen suggested the cause may be GH causing
increased IGF-1 levels, resulting in lymphoid tissue growth
(tonsils/adenoids) which would lead to obstructive sleep
apnea.
• We and others looked at this issue and did find some
association between high IGF-1 levels and tonsil/adenoid
hypertrophy, but no worsening of sleep apnea with GH
treatment.
So….is it risky to start GH?
• There are no difference in the causes of death between
those who are treated with GH vs. those who are not.
• Major causes of mortality in PWS include: respiratory
insufficiency or infection (61% of children), cardiac
arrest, sudden unexplained death, infections, choking
(5-8%), ruptured/necrotic stomach.
• Premature mortality peaks in newborn/early infancy
and adulthood, increased in males – obesity is a factor
in most.
• Therefore, we do need to be cautious when starting GH
in infants and adults, to monitor closely especially
during respiratory infections.
Other Treatments
Provigil (Modafinil)
• Most typical stimulants cause adverse effects in
individual with PWS (skin-picking, tics)
• Provigil works well and thus far, has been safe
and effective in this population.
• Has shown significant benefit when given prior
to therapies and also helping with cognition in
school.
• Can robustly activate fronto-cortical areas
involved in higher cognitive functions and a
network of pro-arousing areas
• Risk of severe allergic reaction/rash in young
children.
Modafinil
• Double-blind placebo controlled studies
indicate that modafinil improves visuospacial
memory accuracy and problem solving ability.
• Improves mood and improves responsiveness
to SSRI’s for patients with depression.
• Improves planning and decision making.
• Improves enjoyment of task performance.
• May help impulse control.
Modafinil
• The memory enhancing properties might be
the result of glutamatergic and dopaminergic
increased neuronal activation in the
hippocampus and in the prefrontal cortex
respectively.
• Other neurotransmitters are also activated by
modafinil in various limbic brain areas,
suggesting that the drug acts on these brain
regions to influence emotional responses.
Modafinil
• Needs research to determine if these effects
exist in PWS and if they may be amplified or
attenuated in children with PWS.
N-acetylcysteine
• Through its role as a modulator of the glutamatergic
system, cysteine influences the reward-reinforcement
pathway.
• Because of these functions, NAC may exert a therapeutic
effect on psychiatric disorders allegedly related to
oxidative stress (e.g., schizophrenia, bipolar disorder) as
well as psychiatric syndromes characterized by
impulsive/compulsive symptoms (e.g., trichotillomania,
pathological nail biting, gambling, substance misuse).
N-acetylcysteine
NAC
• More research needs to be done to determine
if it will increase BDNF in PWS.
• Other info: NAC can be oxidized easily, so if it
smells bad it means it has been oxidized and is
not as effective.
• Pharma-NAC comes in individually sealed
packets, so won’t be oxidized prior to use.
Before and After
New research into hyperphagia
treatments
Hyperphagia Conference
• Much discussion about how to define
hyperphagia and what tests to use to
determine if medications are decreasing
hyperphagia.
• Mouse models are good to use to start with
for treatments, but not always representative
of what will happen in humans.
FDA-approved medications
• There are some already approved medications
that may help with hyperphagia in PWS:
– Metformin
– Diazoxide
Metformin Effects on interest in food
Changes in hyperphagia questionnaire in children with PWS
before and after metformin
3.5
3
Amount of change
2.5
Pt 1
Pt 3
2
Pt 5
Pt 6
1.5
Pt 8
Pt 9
1
Pt 10
Pt 12
0.5
Pt 13
0
Becomes upset
when denied food
Time thinking
Time talking about Anxiety about
Leaving food on
about food
food
meals/eating
plate
Questions with the most change before and after metformin
Feeling full
Metformin – other effects
• Decreases Alzheimer’s disease risk in obese
mice with leptin resistance.
• Reduces risk of some cancers.
• Prevents ghrelin signaling pathway in
hypothalamus.
Diazoxide
• The molecular endpoint of the leptin signaling
pathway in hypothalamic neurons seems to be
the K+-ATP channel.
• Loss of Magel-2 gene appears to disrupt the
leptin signaling pathway, which leads the body to
believe that it’s in a constant state of starvation
and contributes to:
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hyperphagia,
increased rate of adipose tissue deposition,
decreased metabolic rate,
abnormalities of the autonomic nervous system,
growth hormone deficiency.
Diazoxide
• Diazoxide is a K+-ATP channel agonist, so may
bypass the signaling defect in PWS and
compensate for the absent leptin signal in the
hypothalamus.
• In studies of rats and chickens diazoxide
treatment decreased hyperphagia significantly.
Hypoglycemia
• Hypoglycemia appears to play a role in the
appetite and weight issues in PWS
• Recent study indicates that 12% of infants had
severe hypoglycemia (Blood Glucose <40
mg/dL) in newborn period
• Those who had hypoglycemia seem to have a
more difficult time with weight control and
possibly behaviors as they get older.
• Diazoxide increases blood glucose levels
Diazoxide – other effects
• K+-ATP channels in the plasma membrane and
inner mitochondrial membrane play
important roles in modulating neuronal
excitability, cell survival, and cerebral vascular
tone, so diazoxide may ameliorate effects of
Alzheimer’s disease.
• Individuals with PWS may be at higher risk for
premature dementia/Alzheimer’s.
White matter lesions in PWS
Other Medications
• Several potentially promising medications for
hyperphagia including oxytocin, carbetocin, and
other newer medications.
• Some of these medications lower ghrelin which
may work in conjunction with GH (which lowers
ghrelin) to decrease hyperphagia in PWS.
• Others may work more on body weight and have
a secondary effect of decreasing hyperphagia by
increasing signals of satiety to the brain.
Medications for hyperphagia
• Some medications may be able to be used in
certain circumstances to reduce appetite but
may have undesirable side effects if used long
term.
Oxytocin
• Preliminary studies in adults suggest that OT may
decrease appetite, as well as decreasing
depressive symptoms and tantrums while
increasing trust.
• In infants OT may help decrease high ghrelin
levels which may be beneficial in preventing
hyperphagia later in life
• Dosing regimen still uncertain – some doses
appear to be ineffective
• Studies of 5-10 year olds starting soon through
the RDCRN
Oxytocin Update
• We have been working since April 2012 to
start this trial, hoping to start March-June
2013 depending on paperwork progress/IRB.
• For example: oxytocin could potentially cause
low sodium levels (seizures). Also, medications
from compounding pharmacies could be
contaminated and dangerous.
Carbetocin
• Safer than oxytocin in terms of potential side
effects.
• Ferring Pharmaceuticals in interested in trial in
PWS.
• Will need to start with adults in phase 3.
• Working on FDA-approval for trial in PWS.
Beloranib
• IND application and orphan-drug application
for PWS pending.
• Plans for study at UF to begin in March 2013.
• Adults with obesity and hyperphagia who are
able to be seen weekly in Gainesville for 12
week study.
• Plan to enroll 20 adults for trial.
Other Medications
• Lorcaserin: selective serotonin 2C receptor
agonist
• Qnexa: phenteramine and topiramate
• Contrave: buproprion and naltrexone
• Exenatide: Delays gastric emptying, causes
improvement in hypothalamic perception of
satiety.
Current Projects at UF
• Natural History study on effects of GH (infantsadults)
• Oxytocin (ages 5-10)
• Hypoglycemia and Diazoxide (infants – adults)
• Metabolomics in PWS vs. Siblings (infants –
adults)
• Ketogenic diet (ages 5-30)
• Orexin (infants – adults)