scientific background for developing oral levosimendan ......levosimendan for the treatment of als:...
TRANSCRIPT
th28 International Symposium on ALS/MND, Boston, USA, 8-10 December 2017
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Levosimendan is currently registered as a 24-hour IV infusion for the short-term treatment of acutely decompensated severe chronic heart failure in > 60 countries.
The cumulative post-marketing exposure of IV levosimendan is well over 1 million patient days.
Oral levosimendan is now under development for the symptomatic treatment of Amyotrophic Lateral Sclerosis (ALS).
To provide scientific support for developing oral levosimendan for the treatment of ALS.
Literature review and an experimental study in an antibody induced Myasthenia Gravis (MG).
The following properties and studies with levosimendan are providing solid scientific background for developing oral levosimendan for the treatment of ALS:
Levosimendan is a calcium sensitizer binding selectively to troponin C
Levosimendan does not cross blood-brain-barrier 1
Levosimendan does not increase oxygen consumption
Levosimendan has been shown (ex vivo) to improve submaximal force of diaphragm muscle fibres by 15-25%
2obtained from healthy and heart failure rats
Levosimendan has been shown (ex vivo) to improve submaximal force of diaphragm muscle fibres by 25% obtained
3from patients with COPD undergoing lung cancer surgery
These improvements in submaximal force generation are seen 2-3equally in slow and fast muscle fibres
A short IV infusion of levosimendan has been reported to improve neuromechanical efficiency of diaphragm by 21% in healthy
4volunteers
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In Myasthenia Gravis (MG), acetylcholine receptors in neuromuscular junction are blocked by autoantibodies thus functionally mimicking impaired motor neuron function in ALS.
In the antibody induced MG rat model, levosimendan (0.25 mg/kg) improved exercise endurance in a treadmill at 2 hours after a single oral dose (44 ± 66 sec, p=0.06, n=4) when compared to vehicle (-129 ± 46 sec, n=5).
These results suggest that levosimendan improves skeletal muscle function in the rat MG model.
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Levosimendan improves force generation of both slow and fast skeletal muscles. This has been shown both in rat and human skeletal muscles. Levosimendan does not increase oxygen consumption and does not cross the blood-brain-barrier.
There is strong scientific evidence supporting clinical development of oral levosimendan to improve respiratory and skeletal muscle function for the symptomatic treatment of ALS.
1. Ukkonen H, Saraste M, Akkila J et al Clin Pharmacol Ther 2000;68:522-531
2. Van Hees HW, Acuña A, Linkels M et al Brit J Pharmacol 2011; 162:566–573
3. Van Hees HW, PNR Dekhuijzen, LMA Heunks et al Am J Respir Crit Care Med 2009; 179:41-47
4. Doorduin J, Sinderby CA, Beck J et al Am J Respir Crit Care Med 2012; 185:90-95
BACKGROUND
OBJECTIVES
METHODS
RESULTS
DISCUSSION AND CONCLUSIONS
REFERENCES
Table 1. Basic properties of levosimendan.
Properties Levosimendan
Calcium sensitization +
Effect on fast muscle fibers +
Effect on slow muscle fibers +
Long-acting metabolite +
No increase in ATP/oxygen consumption +
Does not cross BBB +
Figure 1. Levosimendan improves exercise endurance in the antibody induced MG model.
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Levosimendan
p=0.06
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Scientific background for
developing oral levosimendan (ODM-109) for
the treatment of Amyotrophic Lateral Sclerosis1 1 1 1 1 1 1 1 2Kuoppamäki M , Lindstedt K , Levijoki J , Hanni O , Nyman L , Pesonen U , Kivikko M , Rouru J , Mervaala E
1 2 Orion Pharma, Espoo and Turku, Finland; University of Helsinki, Helsinki, Finland