An Update on the Clinical Studies Using Arimoclomol as a ...
[Pages:20]An Update on the Clinical Studies Using Arimoclomol as a Potential Treatment for Sporadic Inclusion Body Myositis
Presented to Myositis Support & Understanding (MSU)
Presented by
Mazen Dimachkie, MD
Professor of Neurology, Director of the Neuromuscular Division University of Kansas Medical Center Principal Investigator of Phase II/III Studies of Arimoclomol in IBM
STRICTLY PRIVATE & CONFIDENTIAL
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Presenter Disclosures & Acknowledgements
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nConsulting: Alnylam, Audentes, CSL-Behring, Sanofi Genzyme, Momenta, NuFactor, RMS Medical, Shire Takeda and Terumo.
nResearch funding: Alexion, Alnylam, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, CSL-Behring, FDA/OPD, GlaxoSmithKline, Genentech, Grifols, MDA, NIH, Novartis, Genzyme, Octapharma, Orphazyme, UCB Biopharma, Viromed and TMA.
nEditorial: Journal of clinical neuromuscular disease
nThe phase II/III study of arimoclomol for IBM is co-funded by Orphazyme and an FDA OPD RO1 grant
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Our discussion today
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1
A Leading Theory on the Underlying Problem in Inclusion Body Myositis (IBM)
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Understanding a Natural Defense Mechanism of the Cell
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What We Know About This Defense Mechanism and How it Could be Used in Treating Diseases
4
How this Approach with Arimoclomol is Thought to Work in IBM
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Update on the Progress of the Clinical Studies with Arimoclomol
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Brief overview of sporadic Inclusion Body Myositis (sIBM)
Healthy Muscle
Border of muscle bundle Normal muscle
fibres
Blood vessel
Inclusion Body Myositis
Inclusion bodies
Vacuoles
Degenerative features are evident from protein mishandling: rimmed vacuoles and clusters of
protein deposit inside the cells
n Muscle disorder leading to progressive weakness and loss of muscle mass
n Typically the weakness arises in the quadriceps leading to difficulties in rising from seated position or grip weakness
n In addition weakness of throat muscles can affect swallowing and breathing and will occur in late stages of the disease
Sporadic in this context means not inherited based on known simple gene defect
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Muscle cell pathology suggests that protein dysfunction may be a major underlying cause of IBM
Evidence for both inflammatory and degenerative changes
CD8+ T-Cell
100?m
Ragged-blue fibres
Inflammatory
Degenerative
Mitochondrial
Several clinical trials in IBM -- all targeting inflammatory component: no clinical benefit
A lack of success targeting inflammatory components of the disease prompted us to consider repairing protein dysfunction
as potential therapeutic target
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A leading theory of the underlying problem in IBM is the body's inability to process proteins, leading to the formation of inclusion bodies (protein aggregates) in cells
TDP-43 & other proteins are
processed and folded
abnormally
These proteins aggregate and stress the muscle
cells
Loss of cell function
Proteins incorrectly folded or improperly developed
Leads to protein aggregation, dysfunction,
and cell stress
FOREARM HANDS
THROAT QUADRICEPS
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Activating a natural defense mechanism
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Our cells prefer their environment to be in constant balance--a condition called homeostasis.
Our bodies already know how to try to "fix" or restore cells when stressed by a disease.
? When cells are challenged by pathological stressors, they produce "rescue proteins" to try to protect the cells and restore homeostasis.
? Such stressors could be caused by protein aggregation, a hallmark of IBM
Arimoclomol is being evaluated to understand its
role in amplifying this natural defense mechanism.
? The release of these rescue proteins is called the heat shock response, but also known as the stress response.
The stress response and the rescue protein Heat Shock Protein 70 (HSP 70) have been
well-studied for many years.
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What we know about arimoclomol
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ARIMOCLOMOL
Orally Available
Thought to work by amplifying
the stress response rescue mechanism,
enabling clearance of protein aggregates that accumulate in
the muscle.
A heatshock protein amplifier
Safety Database
279 human subjects have been exposed to arimoclomol, including 112 healthy volunteers and 167 patients with Niemann Pick C, ALS, sIBM
Arimoclomol is taken by mouth 3 times a day
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