Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy

Enrico Bertini, Eric Dessaud, Eugenio Mercuri, Francesco Muntoni, Janbernd Kirschner, Carol Reid, Anna Lusakowska, Giacomo P. Comi, Jean Marie Cuisset, Jean Louis Abitbol, Bruno Scherrer, Patricia Sanwald Ducray, Jeppe Buchbjerg, Eduardo Vianna, W. Ludo van der Pol, Carole Vuillerot, Thomas Blaettler, Paulo Fontoura, Carole André, Claudio Bruno & 19 others Brigitte Chabrol, Nicolas Deconinck, Brigitte Estournet, Stephanie Fontaine-Carbonnel, Nathalie Goemans, Ksenija Gorni, Alessandra Govoni, Michela Guglieri, Hanns Lochmuller, Francesca Magri, Michele Mayer, Wolfgang Müller-Felber, François Rivier, Helen Roper, Ulrike Schara, Mariacristina Scoto, Leonard van den Berg, Giuseppe Vita, Maggie C. Walter

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600. Findings The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding AFM Téléthon and Trophos SA.
Original languageEnglish
Pages (from-to)513-522
Number of pages10
JournalThe Lancet Neurology
Volume16
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

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Spinal Muscular Atrophies of Childhood
Safety
Spinal Muscular Atrophy
Placebos
Outcome Assessment (Health Care)
olesoxime
Nasopharyngitis
Therapeutics
Motor Neuron Disease
Belgium
Poland
Drug Delivery Systems
Random Allocation
Life Expectancy
Cough
Netherlands
Italy
Population
France
Vomiting

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Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy. / Bertini, Enrico; Dessaud, Eric; Mercuri, Eugenio; Muntoni, Francesco; Kirschner, Janbernd; Reid, Carol; Lusakowska, Anna; Comi, Giacomo P.; Cuisset, Jean Marie; Abitbol, Jean Louis; Scherrer, Bruno; Ducray, Patricia Sanwald; Buchbjerg, Jeppe; Vianna, Eduardo; van der Pol, W. Ludo; Vuillerot, Carole; Blaettler, Thomas; Fontoura, Paulo; André, Carole; Bruno, Claudio; Chabrol, Brigitte; Deconinck, Nicolas; Estournet, Brigitte; Fontaine-Carbonnel, Stephanie; Goemans, Nathalie; Gorni, Ksenija; Govoni, Alessandra; Guglieri, Michela; Lochmuller, Hanns; Magri, Francesca; Mayer, Michele; Müller-Felber, Wolfgang; Rivier, François; Roper, Helen; Schara, Ulrike; Scoto, Mariacristina; van den Berg, Leonard; Vita, Giuseppe; Walter, Maggie C.

In: The Lancet Neurology, Vol. 16, No. 7, 01.07.2017, p. 513-522.

Research output: Contribution to journalArticle

Bertini, E, Dessaud, E, Mercuri, E, Muntoni, F, Kirschner, J, Reid, C, Lusakowska, A, Comi, GP, Cuisset, JM, Abitbol, JL, Scherrer, B, Ducray, PS, Buchbjerg, J, Vianna, E, van der Pol, WL, Vuillerot, C, Blaettler, T, Fontoura, P, André, C, Bruno, C, Chabrol, B, Deconinck, N, Estournet, B, Fontaine-Carbonnel, S, Goemans, N, Gorni, K, Govoni, A, Guglieri, M, Lochmuller, H, Magri, F, Mayer, M, Müller-Felber, W, Rivier, F, Roper, H, Schara, U, Scoto, M, van den Berg, L, Vita, G & Walter, MC 2017, 'Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy', The Lancet Neurology, vol. 16, no. 7, pp. 513-522. https://doi.org/10.1016/S1474-4422(17)30085-6
Bertini, Enrico ; Dessaud, Eric ; Mercuri, Eugenio ; Muntoni, Francesco ; Kirschner, Janbernd ; Reid, Carol ; Lusakowska, Anna ; Comi, Giacomo P. ; Cuisset, Jean Marie ; Abitbol, Jean Louis ; Scherrer, Bruno ; Ducray, Patricia Sanwald ; Buchbjerg, Jeppe ; Vianna, Eduardo ; van der Pol, W. Ludo ; Vuillerot, Carole ; Blaettler, Thomas ; Fontoura, Paulo ; André, Carole ; Bruno, Claudio ; Chabrol, Brigitte ; Deconinck, Nicolas ; Estournet, Brigitte ; Fontaine-Carbonnel, Stephanie ; Goemans, Nathalie ; Gorni, Ksenija ; Govoni, Alessandra ; Guglieri, Michela ; Lochmuller, Hanns ; Magri, Francesca ; Mayer, Michele ; Müller-Felber, Wolfgang ; Rivier, François ; Roper, Helen ; Schara, Ulrike ; Scoto, Mariacristina ; van den Berg, Leonard ; Vita, Giuseppe ; Walter, Maggie C. / Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy. In: The Lancet Neurology. 2017 ; Vol. 16, No. 7. pp. 513-522.
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abstract = "Background Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600. Findings The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96{\%} CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding AFM T{\'e}l{\'e}thon and Trophos SA.",
author = "Enrico Bertini and Eric Dessaud and Eugenio Mercuri and Francesco Muntoni and Janbernd Kirschner and Carol Reid and Anna Lusakowska and Comi, {Giacomo P.} and Cuisset, {Jean Marie} and Abitbol, {Jean Louis} and Bruno Scherrer and Ducray, {Patricia Sanwald} and Jeppe Buchbjerg and Eduardo Vianna and {van der Pol}, {W. Ludo} and Carole Vuillerot and Thomas Blaettler and Paulo Fontoura and Carole Andr{\'e} and Claudio Bruno and Brigitte Chabrol and Nicolas Deconinck and Brigitte Estournet and Stephanie Fontaine-Carbonnel and Nathalie Goemans and Ksenija Gorni and Alessandra Govoni and Michela Guglieri and Hanns Lochmuller and Francesca Magri and Michele Mayer and Wolfgang M{\"u}ller-Felber and Fran{\cc}ois Rivier and Helen Roper and Ulrike Schara and Mariacristina Scoto and {van den Berg}, Leonard and Giuseppe Vita and Walter, {Maggie C.}",
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T1 - Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy

AU - Bertini, Enrico

AU - Dessaud, Eric

AU - Mercuri, Eugenio

AU - Muntoni, Francesco

AU - Kirschner, Janbernd

AU - Reid, Carol

AU - Lusakowska, Anna

AU - Comi, Giacomo P.

AU - Cuisset, Jean Marie

AU - Abitbol, Jean Louis

AU - Scherrer, Bruno

AU - Ducray, Patricia Sanwald

AU - Buchbjerg, Jeppe

AU - Vianna, Eduardo

AU - van der Pol, W. Ludo

AU - Vuillerot, Carole

AU - Blaettler, Thomas

AU - Fontoura, Paulo

AU - André, Carole

AU - Bruno, Claudio

AU - Chabrol, Brigitte

AU - Deconinck, Nicolas

AU - Estournet, Brigitte

AU - Fontaine-Carbonnel, Stephanie

AU - Goemans, Nathalie

AU - Gorni, Ksenija

AU - Govoni, Alessandra

AU - Guglieri, Michela

AU - Lochmuller, Hanns

AU - Magri, Francesca

AU - Mayer, Michele

AU - Müller-Felber, Wolfgang

AU - Rivier, François

AU - Roper, Helen

AU - Schara, Ulrike

AU - Scoto, Mariacristina

AU - van den Berg, Leonard

AU - Vita, Giuseppe

AU - Walter, Maggie C.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600. Findings The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding AFM Téléthon and Trophos SA.

AB - Background Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600. Findings The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding AFM Téléthon and Trophos SA.

U2 - 10.1016/S1474-4422(17)30085-6

DO - 10.1016/S1474-4422(17)30085-6

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VL - 16

SP - 513

EP - 522

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

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ER -