essentialis changing the course of chronic disease presentation to fpwr conference november 2014 1...

EssentialisChanging the course of chronic disease

Presentation to FPWR ConferenceNovember 2014

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Update on clinical study PC025


IntroductionMOA in Prader-Willi syndromePC025 Interim Results

Agenda

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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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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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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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Agenda

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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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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


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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


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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Agenda

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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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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


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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


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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)


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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%


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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!”


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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


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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


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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


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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essentialis changing the course of chronic disease presentation to fpwr conference november 2014 1...

Documents

chronic use

essentialis carlsbad

fat stores fat stores

pws dccr

use of fat

fuel dccr

clinical study pc025

aggressive behaviors