Table 2. The most common adverse events (n (%)) reported during the double-blind, crossover part of the study.

Adverse event Treatment

1 mg 2 mg Placebo

N=59 N=59 N=58

Headache 10 (16.9) 17 (28.8) 2 (3.4)

Fall 9 (15.3) 9 (15.3) 5 (8.6)

Increased heart rate* 3 (5.1) 11 (18.6) 1 (1.7)

Nasopharyngitis 4 (6.8) 4 (6.8) 3 (5.2)

Cough 6 (10.2) - 1 (1.7)

Contusion 2 (3.4) 4 (5.1) 1 (1.7)

Nausea 4 (6.8) 1 (1.7) 1 (1.7)

Diarrhoea 1 (1.7) 3 (5.1) 2 (3.4)

Constipation 2 (3.4) 2 (3.4) 3 (5.2)

Oxygen saturation decreased** 3 (5.1) 4 (6.8) -

th28 International Symposium on ALS/MND, Boston, USA, 8-10 December 2017

Levosimendan (i.v.) is approved for the acute worsening of severe chronic heart failure (CHF) in over 60 countries. Levosimendan sensitizes also skeletal muscle fibres to

1-3calcium by binding selectively to troponin C . Based on these findings, oral levosimendan (ODM-109) is now under development in ALS.

To study oral levosimendan in a phase 2 study (LEVALS) in ALS.

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LEVALS was a randomized, double-blind, placebo-controlled, 3-period, cross-over phase 2 study with a 6 month open-label extension

Study treatments were placebo and 1 mg and 2 mg daily doses of levosimendan

Each treatment period lasted for 14 days separated by wash-out periods

Primary endpoint was sitting SVC and secondary endpoints included e.g. supine SVC and ALSFRS-R

Main inclusion criterion was sitting SVC between 60-90% predicted at screening

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66 patients were randomized. 59 patients contributed to the double-blind results and 50 completed all three treatment periods.

Primary endpoint sitting SVC: Period 1 Day 1 was the originally defined baseline for all periods. However, there was a clear period effect in the data. Therefore period-wise baselines were justified in the analyses (post-hoc). The estimated mean differences from baseline were 0.67, -0.98 and -0.01 % points for placebo, levosimendan 1 mg daily (p = 0.97 vs. placebo) and levosimendan 2 mg daily (p = 0.85 vs. placebo), respectively.

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For the supine SVC (post-hoc), the estimated mean differences from period-wise baseline were -3.62, +0.77 and +2.38 % points for placebo, levosimendan 1 mg daily (p = 0.018 vs. placebo) and levosimendan 2 mg daily (p = 0.001 vs. placebo), respectively (Fig 2).

Both levosimendan doses were numerically better compared to placebo in ALSFRS-R total score. The estimated mean differences from baseline were -0.82, -0.46 and -0.37 for placebo, levosimendan 1 mg daily (p = 0.49 vs. placebo) and levosimendan 2 mg daily (p = 0.34 vs. placebo), respectively. Similar trends were seen also in the respiratory domain scores.

There were no significant differences between the treatments in other secondary endpoints such as SNP, grip strength, overnight SpO2, CGI-C and QoL.

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Levosimendan was generally well tolerated. The most common adverse events (AEs) reported as related to levosimendan were headache (due to vasodilatation) and increase in heart rate (HR) with dose-dependent increase in frequency.

AEs leading to discontinuation were reported in 1, 10 and 2 subjects during levosimendan 1 mg, levosimendan 2 mg and placebo treatments, respectively. Discontinuations were mainly due to increased heart rate.

The number of severe AEs, serious AEs (SAEs) and supraventricular and ventriculartachyarrhythmias were similar between placebo and levosimendan treatments.

Levosimendan does not cross BBB and therefore there were only few CNS related adverse events reported.

Although the primary endpoint of sitting SVC did not find differences between the treatments, there was a promising signal in supine SVC. Supine SVC results indicated dose-related treatment effects favoring levosimendan treatments over placebo. Measuring SVC in supine position is clinically relevant, because often the signs of respiratory insufficiency appear when lying down. There is evidence that vital capacity (VC) measured in supine position correlates better with diaphragmatic weakness than

4that measured in upright position and is a better predictor of survival compared with 5-6upright VC . Levosimendan was well tolerated, headache and tachycardia being the

most common AEs.

1. Van Hees HW, Acuña A, Linkels M et al Brit J Pharmacol 2011; 162:566–573

2. Van Hees HW, PNR Dekhuijzen, LMA Heunks et al Am J Respir Crit Care Med 2009; 179:41-47

3. Doorduin J, Sinderby CA, Beck J et al Am J Respir Crit Care Med 2012; 185:90-95

4. Lechtzin N, Wiener CM, Shade DM et al Chest 2002; 121:436-442

5. Schmidt EP, Drachman DB, Wiener CM et al Muscle Nerve 2006; 33:127-132

6. Baumann F, Henderson RD, Stephen SC et al ALS 2010; 11:194-202

BACKGROUND

OBJECTIVES

METHODS

EFFICACY RESULTS

DISCUSSION AND CONCLUSIONS

TOLERABILITY AND SAFETY

REFERENCES

Table 1. Baseline charactristics, N=66

Figure 1. The two baseline definitions and the corresponding supine SVC data.

Figure 2. Supine SVC in the double-blind, crossover part of the study.

Variable

Age, yearsMedian 56.5

Range 36-75

Sex, n (%)Male 47 (71.2)

Female 19 (28.8)

Weight, kg Mean (SD) 76.7 (15.9)

2BMI, kg/m Mean (SD) 25.6 (4.0)

Disease duration from symptom onset, monthsMedian 21.2

Range 12-48

Sitting SVC % of predicted Mean (SD) 75.3 (9.1)

Supine SVC % of predicted Mean (SD) 73.3 (14.0)

ALSFRS-R total score Mean (SD) 36.7 (5.4)

Oral levosimendan (ODM-109): Key placebo-controlled results from the phase 2 study in ALS patients with SVC between 60-90% predicted at screening

1 2 3 4 5 6 7 7Ammar Al-Chalabi, Pamela Shaw, P. Nigel Leigh, Leonard van den Berg, Orla Hardiman, Albert Ludolph, Toni Sarapohja, Mikko Kuoppamäki 1 2 3 King's MND Care and Research Centre, King's College London, UK, Sheffield Institute for Translational Neuroscience, University of Sheffield, UK, Brighton and Sussex Medical School, University of Sussex,

4 5 6 7UK, University Medical Center Utrecht, Netherlands, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland, Department of Neurology, University of Ulm, Germany, Orion Pharma, Finland

* AE includes terms ‘increased heart rate’, ‘tachycardia’ and ‘sinus tachycardia’.

**Decreased oxygen saturation was reported in a total of 2 patients from 2 centers

Levosimendan 1 mg b.i.d. Levosimendan 1 mg Placebo

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