nothing is perfect problems with triheptanoin and clinical ... · problems with triheptanoin and...
TRANSCRIPT
Joerg Klepper
bdquonothing is perfectldquo ndashProblems with triheptanoin
and clinical trials
MILAN Italy 7th ndash 8th October 2016
The State-and-Region Agreement asks for a declaration by Moderators Speakers Teachers and Tutors about the frankness of the financing sources and about
their relationships with people with commercial interests within the last two years only if there could be a conflict of interests
The documents must be available at the Provider offices for at least 5 years
Conflict of Interests Declaration
Undersigned Prof Dr med Joerg Klepper as
x scientific responsible x moderator teacher x speaker tutor
of the event ldquo1st European Conference on Glut1 Deficiencyrdquo
Milan - Italy 7th-8th October 2016
Based on Art 33 about the Conflict of Interests page 1819 of the State-and-Region Agreement dated 19 April 2012
managed by Biomedia n 148
Declares
x that in the last two years HAD relationships about comercial financings with people having conflict of interests in the health field
(please specify the names)
Nutricia GmbH Erlangen Germany travel costs and speaker honoraria
Vitaflo Pharma GmbH Bad Homburg vor der Houmlhe Germany travel costs and speaker honoraria
The State-and-Region Agreement asks for a declaration by Moderators Speakers Teachers and Tutors about the frankness of the financing sources and about
their relationships with peop le with commercial interests within the last two years only if there could be a conflict of interests
The documents must be available at the Provider offices for at least 5 years
SLIDE N2
Undersigned
First name ___Joerg_______________________ Surname ________Klepper_____________________
Declares under his responsibility that in the report entitled
ldquoNothing is perfect ndash problems with Triheptanoin and clinical trials in Glut1DSrdquo
There will be named the following Companies and or Commercial Products
Ultragenyx Pharmaceutical Inc Novato USA
_______________________________
JUST WITH AN EDUCATIONAL AND SCIENTIFIC AIM OR TO REFER TO NATIONAL OR INTERNATIONAL GUIDELINES
Triheptanoin bdquoC7ldquo
Triheptanoin bull C7-ketoester (bdquoartificial ketoneldquo)
bull used as tracer for butter in the EU
bull liquid at RT with indifferent taste
OO C7
O O
O O
O
O
O
OO O
C7
C7
Roe CR Brunengraber HAnaplerotic treatment of long-chain fat oxidation disorders with triheptanoin Review of 15 years Experience Mol Genet Metab 2015 Dec116(4)260-8
Triheptanoin bdquoC7ldquo
Triheptanoin
O O
O O
O
O
100 oxygen
+ C7
ANAPLEROSIS
bdquoplushellipldquo bdquoketoneldquo
Triheptanoin bdquoC7ldquoO O
O O
O
O
TCAcycle
ATP
Acetyl-CoA
C7
bdquooddldquo carbons
triheptanoin
C16
bdquoevenldquo carbons
Fatty acid
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
The State-and-Region Agreement asks for a declaration by Moderators Speakers Teachers and Tutors about the frankness of the financing sources and about
their relationships with people with commercial interests within the last two years only if there could be a conflict of interests
The documents must be available at the Provider offices for at least 5 years
Conflict of Interests Declaration
Undersigned Prof Dr med Joerg Klepper as
x scientific responsible x moderator teacher x speaker tutor
of the event ldquo1st European Conference on Glut1 Deficiencyrdquo
Milan - Italy 7th-8th October 2016
Based on Art 33 about the Conflict of Interests page 1819 of the State-and-Region Agreement dated 19 April 2012
managed by Biomedia n 148
Declares
x that in the last two years HAD relationships about comercial financings with people having conflict of interests in the health field
(please specify the names)
Nutricia GmbH Erlangen Germany travel costs and speaker honoraria
Vitaflo Pharma GmbH Bad Homburg vor der Houmlhe Germany travel costs and speaker honoraria
The State-and-Region Agreement asks for a declaration by Moderators Speakers Teachers and Tutors about the frankness of the financing sources and about
their relationships with peop le with commercial interests within the last two years only if there could be a conflict of interests
The documents must be available at the Provider offices for at least 5 years
SLIDE N2
Undersigned
First name ___Joerg_______________________ Surname ________Klepper_____________________
Declares under his responsibility that in the report entitled
ldquoNothing is perfect ndash problems with Triheptanoin and clinical trials in Glut1DSrdquo
There will be named the following Companies and or Commercial Products
Ultragenyx Pharmaceutical Inc Novato USA
_______________________________
JUST WITH AN EDUCATIONAL AND SCIENTIFIC AIM OR TO REFER TO NATIONAL OR INTERNATIONAL GUIDELINES
Triheptanoin bdquoC7ldquo
Triheptanoin bull C7-ketoester (bdquoartificial ketoneldquo)
bull used as tracer for butter in the EU
bull liquid at RT with indifferent taste
OO C7
O O
O O
O
O
O
OO O
C7
C7
Roe CR Brunengraber HAnaplerotic treatment of long-chain fat oxidation disorders with triheptanoin Review of 15 years Experience Mol Genet Metab 2015 Dec116(4)260-8
Triheptanoin bdquoC7ldquo
Triheptanoin
O O
O O
O
O
100 oxygen
+ C7
ANAPLEROSIS
bdquoplushellipldquo bdquoketoneldquo
Triheptanoin bdquoC7ldquoO O
O O
O
O
TCAcycle
ATP
Acetyl-CoA
C7
bdquooddldquo carbons
triheptanoin
C16
bdquoevenldquo carbons
Fatty acid
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
The State-and-Region Agreement asks for a declaration by Moderators Speakers Teachers and Tutors about the frankness of the financing sources and about
their relationships with peop le with commercial interests within the last two years only if there could be a conflict of interests
The documents must be available at the Provider offices for at least 5 years
SLIDE N2
Undersigned
First name ___Joerg_______________________ Surname ________Klepper_____________________
Declares under his responsibility that in the report entitled
ldquoNothing is perfect ndash problems with Triheptanoin and clinical trials in Glut1DSrdquo
There will be named the following Companies and or Commercial Products
Ultragenyx Pharmaceutical Inc Novato USA
_______________________________
JUST WITH AN EDUCATIONAL AND SCIENTIFIC AIM OR TO REFER TO NATIONAL OR INTERNATIONAL GUIDELINES
Triheptanoin bdquoC7ldquo
Triheptanoin bull C7-ketoester (bdquoartificial ketoneldquo)
bull used as tracer for butter in the EU
bull liquid at RT with indifferent taste
OO C7
O O
O O
O
O
O
OO O
C7
C7
Roe CR Brunengraber HAnaplerotic treatment of long-chain fat oxidation disorders with triheptanoin Review of 15 years Experience Mol Genet Metab 2015 Dec116(4)260-8
Triheptanoin bdquoC7ldquo
Triheptanoin
O O
O O
O
O
100 oxygen
+ C7
ANAPLEROSIS
bdquoplushellipldquo bdquoketoneldquo
Triheptanoin bdquoC7ldquoO O
O O
O
O
TCAcycle
ATP
Acetyl-CoA
C7
bdquooddldquo carbons
triheptanoin
C16
bdquoevenldquo carbons
Fatty acid
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin bdquoC7ldquo
Triheptanoin bull C7-ketoester (bdquoartificial ketoneldquo)
bull used as tracer for butter in the EU
bull liquid at RT with indifferent taste
OO C7
O O
O O
O
O
O
OO O
C7
C7
Roe CR Brunengraber HAnaplerotic treatment of long-chain fat oxidation disorders with triheptanoin Review of 15 years Experience Mol Genet Metab 2015 Dec116(4)260-8
Triheptanoin bdquoC7ldquo
Triheptanoin
O O
O O
O
O
100 oxygen
+ C7
ANAPLEROSIS
bdquoplushellipldquo bdquoketoneldquo
Triheptanoin bdquoC7ldquoO O
O O
O
O
TCAcycle
ATP
Acetyl-CoA
C7
bdquooddldquo carbons
triheptanoin
C16
bdquoevenldquo carbons
Fatty acid
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin bdquoC7ldquo
Triheptanoin
O O
O O
O
O
100 oxygen
+ C7
ANAPLEROSIS
bdquoplushellipldquo bdquoketoneldquo
Triheptanoin bdquoC7ldquoO O
O O
O
O
TCAcycle
ATP
Acetyl-CoA
C7
bdquooddldquo carbons
triheptanoin
C16
bdquoevenldquo carbons
Fatty acid
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
ANAPLEROSIS
bdquoplushellipldquo bdquoketoneldquo
Triheptanoin bdquoC7ldquoO O
O O
O
O
TCAcycle
ATP
Acetyl-CoA
C7
bdquooddldquo carbons
triheptanoin
C16
bdquoevenldquo carbons
Fatty acid
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
bdquoAnaplerosisldquohellip a series of pathways that replenish the pools of metabolic intermediates in the TCA cycle
TCAcycle
ATP
bdquofoodldquo
amino-acids
C7
ANAPLEROSIS KATAPLEROSIS
fattyacids
glucose
If intermediates can be added to the TCA cycle it is equally important to remove them
bdquoKataplerosisldquo
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
bdquoAnaplerosisldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS KATAPLEROSIS
bdquoKataplerosisldquo
ldquomore like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out ndashor the entire traffic pattern will be interrupted with disastrous consequencesrdquo
Fed state Ketosis
httpimagesclipartpandacom
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Anaplerosis and cataplerosis in the TCA cycle
Oliver E Owen et al J Biol Chem 200227730409-30412
copy2002 by American Society for Biochemistry and Molecular Biology
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
bdquohow does triheptanoin workldquo
TCAcycle
ATP
bdquofoodldquoANAPLEROSIS
bull thalamusbull neocortical regionsbull cerebellum
Movementcontrol
18F FDG-PET
Akman CI et alEpilepsy Res 2015
triheptanoin
wikipedia
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Pilot trial of Triheptanoin for GLUT1
JAMA Neurol 2014
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Seizure Rate Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
6 wks baseline
Randomisation
OptionalUX007 ff
bdquoopen-lable extension periodldquo=gt All patients on UX007
triheptanoin
8 wks Study
triheptanoin
placebo
Time period Jan ndash Oct 2014Design randomised double-blind placebo-controlled
52 Wks
-Triheptanoin as a) food supplement
b) drug (prescription)
- what happens with the data
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Inclusion criteria
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
ParoxysmalEvents(n = 6)
Mochel F et al J Neurol Neurosurg Psychiatry 2015 Nov 3
Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1
deficiency
baseline treatment withdrawal
Non-epilepticparoxysmalGlut1D(n=8-27-47 yrs)
2m 2m 2m
bdquoProof ofconceptldquo1gkg
Triheptanoin-Study UX007
httprghinl
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin-Study UX007
Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Hypothesis better seizure control
bull n=50 male + female 3 ndash 17 yrsbull SLC2A1+bull at least 5 clinically manifest seizures within 6 months prior to study 4 at baselinebull recurrent seizures despite 1 anticonvulsantbull Co-medication 1-3 anticonvulsants (maintained for study period)bull no KD uncompliant with KD prioron studybull Beta-hydroxybutyrate le 1 mmolL (non-fasting state) at time of screeningbull no trial with triheptanoin
Time period Jan ndash Oct 2014Design randomised double-blinded placebo-controlled
Improves movement disorder
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Rationale a) G1D is drug-refractory b) no other G1D treatment is as versatile as partial dietary fat replacement with C7c) the ketogenic diet is ineffective or intolerable for 13 of G1D patientsd) C7 impacts both neuropsychological performance and EEG spike-waves
Prof PascualDallas Texas
Aims in G1D patients receiving a normal diet
1 determine C7 maximum tolerable dose and safety (primary outcomes)
2 evaluate the effect of partial C7 dietary replacement on
- attention ratings (primary outcome)
- EEG
- neuropsychological neurological performance indices
3 explore C7 compatibility with KDT by evaluating
- EEG
- clinical seizures (primary outcomes)
- ketosis and glycemia
Project Number 1R01NS094257-01A1
DIETARY TREATMENT OF GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY
UT SOUTHWESTERN MEDICAL CENTERKDTC7
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Glut1D Databank
Prof PascualDallas Texas
wwwG1DRegistryorg
Online-QuestionaireIndependent accessible data bank
Unanswered questions
bull How many bull Clinical classification (bdquomissing linkldquo between Glut1D type1+ type2hellip)bull Phenotype-genotype-relationbull Treatment response Non-Respondersbull Long-term adverse effects other tissues affectedbull What happens in pubertybull Transition into adult neurologybull future therapies (triheptanoin)
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Triheptanoin bdquoC7ldquo
PRObull artificial ketonebullbdquoeffectldquo via bdquoanaplerosisldquobull safe few side effects(experience in metabolic disease mouse model (human trial)
O O
O O
O
O
CONbull high quantities neededbull long-term effectsbull no replacement for KDT bull cost and availability
Joergklepperklinikum-ab-alzde
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Patients amp Designbull 14 Glut1D patients (2-28 yrs) prior to KD treatmentbull unsponsored open-label case seriesbull regular food supplement with 075-10 mgkg C7-oil (15-60 ml) single dose
3M 6M
C7
0lsquo 30lsquo 60lsquo 90lsquo 120lsquo
NeuropsychologicalTesting (I)
NeuropsychologicalTesting (II)
C7
EEG recording
MRI MRI
Resultsbull spike-waves by 70 (except in 1 patient)bull neuropsychological performance bull cerebral metabolic rate
bull adverse effects - none (n=11 78)- GI-Symptoms(n=03 21)- discontinued (n=01 07)
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M
Pascual JM et alJAMA Neurol 2014 Aug 11[Epub ahead of print]
Seizure Rate
Conclusionbull Triheptanoin can favorably influence neural function in G1D
Neuropsychological scores
Expressive vocabulary test (EVT-2) Standardized PeabodyPicture vocabulary test (PPVT-4)
0min 60min 3M 0min 60min 3M