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EssentialisChanging the course of chronic disease
Presentation to FPWR ConferenceNovember 2014
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Update on clinical study PC025
EssentialisChanging the course of chronic disease
IntroductionMOA in Prader-Willi syndromePC025 Interim Results
Agenda
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EssentialisChanging the course of chronic disease
Introduction to Essentialis
• Carlsbad, CA based, clinical stage, venture backed drug development company
• Focused on development of activators or openers of the ATP-sensitive potassium (KATP) channel to treat orphan diseases
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EssentialisChanging the course of chronic disease
Products – Based on Patented Active
• Diazoxide choline is a patent protected, proprietary salt of diazoxide
• Formulated as – Once per day tablet – DCCR
• Tested in more than 200 subjects to date
– Oral solution – DCOS– IV solution - DCIV
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EssentialisChanging the course of chronic disease
Diazoxide – Long History of Safe Use
Diazoxide• KATP channel agonist
• IV treatment for malignant hypertension – First Approved 1973 and used through the 80’s,
no longer available• Oral suspension for the treatment of insulinoma in
adults and CHI in neonates and children – Approved 1976 and remains standard of care
globally• More than 110,000 patient-years of chronic use
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EssentialisChanging the course of chronic disease
IntroductionMOA in Prader-Willi syndromePC025 Interim Results
Agenda
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EssentialisChanging the course of chronic disease
Hyperphagia in PWS is most likely due to dysregulation of neurons in the hypothalamus
Appetite
Reduced food intake
Dysregulation of AgRP and POMC neurons will result in increased food intake and reduced energy expenditure
DCCR may reduce this dysregulation
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EssentialisChanging the course of chronic disease
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DCCR has peripheral impacts that complement the central effect
Long Chain fatty acids
Triglycerides
Energy production
Acetyl-CoA
Fatty acids
Triglycerides
Synthesis of fat Use of fat as fuel
DCCR coordinately down-regulates de-
novo synthesis of fatty acids by down
regulating ACCase and FAS and upregulates
β-oxidation of fat reducing fat stores
Fat Stores
EssentialisChanging the course of chronic disease
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DCCR may affect key neurotransmitters• Gamma-amino butyric acid (GABA) is an
important neurotransmitter
• In PWS – The expression of GABA-A receptors is diminished– GABA concentrations are markedly elevated– Likely leads to receptor desensitization– May be associated with aggressive behaviors
• DCCR reduces GABA concentrations, may restore sensitivity, potentially reducing aggressive behaviors
EssentialisChanging the course of chronic disease
DCCR - Mode of Action in PWS• DCCR
– In the hypothalamus• Reduces dysregulation of key neurons - reducing the
central starvation signal
– Peripherally• Coordinately down-regulates synthesis of fats and
upregulates the use of fat as fuel - reducing fat stores
– Centrally• May restore sensitivity to GABA
• Overall– Reduces hyperphagia, increases energy
expenditure, reduces fat mass and weight, may impact aggressive behaviors
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EssentialisChanging the course of chronic disease
IntroductionMOA in Prader-Willi syndromePC025 Interim Results
Agenda
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EssentialisChanging the course of chronic disease
PC025 Pilot StudyOpen label titration followed by randomized withdrawal
Pilot Study of DCCR in obese, genetically confirmed PWS patients between 10 and 22 years
• Being conducted at the University of California, Irvine
• Up to12 patients• Total duration of treatment 14
weeks
• Endpoints: hyperphagia, REE; exploratory – weight, BMI, fat mass, lean body mass, RQ, behaviors, endocrine and glycemic parameters
• Open label dose escalation 1.5 mg/kg to 5 mg/kg (titrated in 4 steps every 2 weeks) – 10 weeks
• Last 4 weeks are a double-blind, placebo-controlled, randomized withdrawal extension– Randomized 1:1 to continue
on dose or receive placebo– 4 additional weeks of
treatment
Recruitment 4 more patients
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EssentialisChanging the course of chronic disease
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Schematic of study
Screening
(up to 4 wks)
Open Label Treatment Period(10 wks)
Double-Blind, Placebo-
Controlled, Randomized Withdrawal Extension
(4 wks)
4 wks
Base
line
Day 0
2 wks 2 wks 2 wks 2 wks 2 wks 4 wks
1.5 mg/kg
2.4 mg/kg
3.3 mg/kg
4.2 mg/kg
5.1 mg/kg
5.1 mg/kg
Day 55 dose or Placebo
Equivalent for Responders
and
Day 55 dose for Non-
Responders
EssentialisChanging the course of chronic disease
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Efficacy endpoints in PC025
Parameter Measured by Measured at
Hyperphagia Questionnaire Every visit
Body fat DEXA Screening or Baseline, 10 wks
Lean body mass DEXA Screening or Baseline, 10 wks
Behaviors Questionnaire Screening and 10 wks
Weight Scale Every visit
Resting energy expenditure
Indirect calorimetry
Baseline, 4 wks, 8 wks, 10 wks, 14 wks
Respiratory quotient
Indirect calorimetry
Baseline, 4 wks, 8 wks, 10 wks, 14 wks
Blood pressure Automated Every visit
Lipids Lab assay Baseline, 10 wks
EssentialisChanging the course of chronic disease
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Patients enrolled in the study to date
Parameter Baseline average (range)
Sex 4 F/6 M
Age 16 yr (11 - 21 yr)
PWS sub-type All deletions
GH treatment 3 Y/7 N
Weight 92.3 kg (56.9 - 133.6 kg)
Percent body fat 53.4 % (42.9 – 60.7%)
BMI 40.1 (25 – 53.8)
Hyperphagia score (0 – 34)
16.4 (3 – 25.5)
EssentialisChanging the course of chronic disease
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PC025 – Hyperphagia: High response rate statistically significant improvements
• Hyperphagia response rate to DCCR is high ~ 87.5%– Statistically significant improvements in hyperphagia
(~33% reduction)– Response is better or more durable in those who
responded with baseline hyperphagia scores below 20
– Initial hyperphagia response observed at the two lowest doses
Baseline hyperphag
ia N
Improvement in
hyperphagia< 20 4 39.7%≥ 20 3 24.0%
EssentialisChanging the course of chronic disease
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Results are confirmed by verbatim statements from parents
• “She never misses her breakfast, lunch, snack, or dinner. Usually she asks for more food. But surprisingly she said she feels full. This has never happened before. She skipped her lunch!”
• “It seems like my child is less interested in food”
• “He is no longer getting up at night for food and digging through the trash!”
EssentialisChanging the course of chronic disease
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Other efficacy responsesEfficacy Parameter Response
Yelling/ aggressive / destructive/ threatening behavior
Stopped
Weight - 1.0 kg
Body fat - 2.4%
Lean body mass +3.33% in GH patients with no change in non-GH
Resting energy expenditure + 90 kcal/day
Fuel source Shift towards burning more fat as fuel
Blood pressure and lipids Improvements are known effect of drug
EssentialisChanging the course of chronic disease
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PC025 – Interim results
• Response occurring at very low doses of DCCR– Below the labeled range of diazoxide in
its approved indication
• Drug appears to be well tolerated
EssentialisChanging the course of chronic disease
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Safety
• The most common adverse events– Peripheral edema
• Often transient• Associated with the blood pressure lowering
effect • Mechanism similar to that of other blood
pressure lowering drugs
– Potential to raise glucose levels• A small subset of patients are particularly
sensitive and can be quickly identified
EssentialisChanging the course of chronic disease
DCCR in PWS Next Steps
• Complete pilot study• Our thinking on the development
plan is evolving as interim data becomes available
• Open a dialogue on development with FDA
• Raise the funds to continue development
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