Review

. 2017 Oct 31;89(18):1915-1922.

doi: 10.1212/WNL.0000000000004606. Epub 2017 Oct 4.

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

Ruben P A van Eijk¹, Ashley R Jones¹, William Sproviero¹, Aleksey Shatunov¹, Pamela J Shaw¹, P Nigel Leigh¹, Carolyn A Young¹, Christopher E Shaw¹, Gabriele Mora¹, Jessica Mandrioli¹, Giuseppe Borghero¹, Paolo Volanti¹, Frank P Diekstra¹, Wouter van Rheenen¹, Esther Verstraete¹, Marinus J C Eijkemans¹, Jan H Veldink¹, Adriano Chio¹, Ammar Al-Chalabi², Leonard H van den Berg¹, Michael A van Es²; For UKMND-LiCALS and LITALS Study Group

Collaborators, Affiliations

Collaborators

For UKMND-LiCALS and LITALS Study Group:
C Allen, C Counsell, A Farrin, A Al-Chalabi, B Dickie, J Kelly, P N Leigh, C L Murphy, C Payan, G Reynolds, P Shaw, I N Steen, M Thornhill, J Waters, J Zajicek, P N Leigh, A Al-Chalabi, P J Shaw, C A Young, M Thornhill, I N Steen, C L Murphy, K E Morrison, S Dhariwal, R Hornabrook, L Savage, D J Burn, T K Khoo, J Kelly, C L Murphy, A Al-Chalabi, A Dougherty, P N Leigh, L Wijesekera, M Thornhill, C M Ellis, R Ali, K O'Hanlon, J Panicker, L Pate, P Ray, L Wyatt, C A Young, L Copeland, J Ealing, H Hamdalla, I Leroi, C Murphy, F O'Keeffe, E Oughton, L Partington, P Paterson, D Rog, A Sathish, D Sexton, J Smith, H Vanek, S Dodds, T L Williams, I N Steen, J Clarke, C Eziefula, R Howard, R Orrell, K Sidle, R Sylvester, W Barrett, C Merritt, K Talbot, M R Turner, C Whatley, C Williams, J Williams, C Cosby, C O Hanemann, I Imam, C Phillips, L Timings, S E Crawford, C Hewamadduma, R Hibberd, H Hollinger, C McDermott, G Mills, M Rafiq, P J Shaw, A Taylor, E Waines, T Walsh, R Addison-Jones, J Birt, M Hare, T Majid, R Tortelli, E D'Errico, I Bartolomei, E Barbarossa, B Depau, E Costantino, E D'Amico, A Uncini, C Manzoli, R Quatrale, E Sette, E Montanari, M Merello, D Zarcone, M Mascolo, M Vignolo, S Messina, C Morelli, K Marinou, L Papetti, C Lunetta, K Gorni, D De Cicco, C Pipia, P Sola, E Georgoulopoulou, A Sagnelli, G Tedeschi, G Oggioni, N Nasuelli, C D'Ascenzo, V Cima, M Aiello, R Rizzi, E Rinaldi, M Luigetti, A Conte, A Torzini, G Greco, R Mutani, G Fuda, M A Tommasi

Affiliations

¹ From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.), Department of Basic and Clinical Neuroscience, King's College London; Sheffield Institute for Translational Neuroscience (SITraN) (P.J.S.), University of Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience (J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della Scienza (A.C.), Turin, Italy.
² From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.), Department of Basic and Clinical Neuroscience, King's College London; Sheffield Institute for Translational Neuroscience (SITraN) (P.J.S.), University of Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience (J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della Scienza (A.C.), Turin, Italy. m.a.vanes@umcutrecht.nl ammar.al-chalabi@kcl.ac.uk.

PMID: 28978660
PMCID: PMC5664299
DOI: 10.1212/WNL.0000000000004606

Review

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

Ruben P A van Eijk et al. Neurology. 2017.

. 2017 Oct 31;89(18):1915-1922.

doi: 10.1212/WNL.0000000000004606. Epub 2017 Oct 4.

Authors

Collaborators

For UKMND-LiCALS and LITALS Study Group:
C Allen, C Counsell, A Farrin, A Al-Chalabi, B Dickie, J Kelly, P N Leigh, C L Murphy, C Payan, G Reynolds, P Shaw, I N Steen, M Thornhill, J Waters, J Zajicek, P N Leigh, A Al-Chalabi, P J Shaw, C A Young, M Thornhill, I N Steen, C L Murphy, K E Morrison, S Dhariwal, R Hornabrook, L Savage, D J Burn, T K Khoo, J Kelly, C L Murphy, A Al-Chalabi, A Dougherty, P N Leigh, L Wijesekera, M Thornhill, C M Ellis, R Ali, K O'Hanlon, J Panicker, L Pate, P Ray, L Wyatt, C A Young, L Copeland, J Ealing, H Hamdalla, I Leroi, C Murphy, F O'Keeffe, E Oughton, L Partington, P Paterson, D Rog, A Sathish, D Sexton, J Smith, H Vanek, S Dodds, T L Williams, I N Steen, J Clarke, C Eziefula, R Howard, R Orrell, K Sidle, R Sylvester, W Barrett, C Merritt, K Talbot, M R Turner, C Whatley, C Williams, J Williams, C Cosby, C O Hanemann, I Imam, C Phillips, L Timings, S E Crawford, C Hewamadduma, R Hibberd, H Hollinger, C McDermott, G Mills, M Rafiq, P J Shaw, A Taylor, E Waines, T Walsh, R Addison-Jones, J Birt, M Hare, T Majid, R Tortelli, E D'Errico, I Bartolomei, E Barbarossa, B Depau, E Costantino, E D'Amico, A Uncini, C Manzoli, R Quatrale, E Sette, E Montanari, M Merello, D Zarcone, M Mascolo, M Vignolo, S Messina, C Morelli, K Marinou, L Papetti, C Lunetta, K Gorni, D De Cicco, C Pipia, P Sola, E Georgoulopoulou, A Sagnelli, G Tedeschi, G Oggioni, N Nasuelli, C D'Ascenzo, V Cima, M Aiello, R Rizzi, E Rinaldi, M Luigetti, A Conte, A Torzini, G Greco, R Mutani, G Fuda, M A Tommasi

Affiliations

¹ From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.), Department of Basic and Clinical Neuroscience, King's College London; Sheffield Institute for Translational Neuroscience (SITraN) (P.J.S.), University of Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience (J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della Scienza (A.C.), Turin, Italy.
² From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.), Department of Basic and Clinical Neuroscience, King's College London; Sheffield Institute for Translational Neuroscience (SITraN) (P.J.S.), University of Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience (J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della Scienza (A.C.), Turin, Italy. m.a.vanes@umcutrecht.nl ammar.al-chalabi@kcl.ac.uk.

PMID: 28978660
PMCID: PMC5664299
DOI: 10.1212/WNL.0000000000004606

Erratum in

Correction: Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.
[No authors listed] [No authors listed] Neurology. 2017 Nov 28;89(22):2303. doi: 10.1212/WNL.0000000000004727. Neurology. 2017. PMID: 29180580 No abstract available.

Abstract

Objective: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.

Methods: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.

Results: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).

Conclusions: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.

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Figures

**Figure 1. Pooled analysis of treatment effect for lithium carbonate and 12-month survival for each genetic subgroup**
Pooled 12-month survival in 3 clinical trials evaluating the efficacy of lithium carbonate. (A) Overall treatment effect of lithium carbonate was nonsignificant (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7–1.4). (B) There was a significant effect of genetic subgroups on 12-month survival, irrespective of treatment arm, within the clinical trials (*UNC13A* HR 2.4, 95% CI 1.3–4.3; p = 0.006; and *C9orf72* HR 2.5, 95% CI 1.1–5.2; p = 0.032). Three patients had both risk variants of *UNC13A* and *C9orf72*; the number at risk of these patients is merged with the *UNC13A* carriers.

**Figure 2. Cox proportional hazards model of 12-month survival and the interaction of lithium carbonate with *UNC13A* genotype**
Incorporating interaction terms between treatment arm (control or active) and *UNC13A* carrier status revealed that the effect of lithium carbonate significantly depended on the *UNC13A* carrier status (p = 0.027). Lithium carbonate improved the 12-month survival in individuals with the *UNC13A C/C* genotype, but had no effect in noncarriers.

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Comment in

The beginning of precision medicine in ALS? Treatment to fit the genes.
Armon C, Hardiman O. Armon C, et al. Neurology. 2017 Oct 31;89(18):1850-1851. doi: 10.1212/WNL.0000000000004612. Epub 2017 Oct 4. Neurology. 2017. PMID: 28978653 No abstract available.

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Hypermetabolism in ALS is associated with greater functional decline and shorter survival.
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Manini A, Casiraghi V, Brusati A, Maranzano A, Gentile F, Colombo E, Bonetti R, Peverelli S, Invernizzi S, Gentilini D, Messina S, Verde F, Poletti B, Fogh I, Morelli C, Silani V, Ratti A, Ticozzi N. Manini A, et al. Front Aging Neurosci. 2023 Feb 1;15:1067954. doi: 10.3389/fnagi.2023.1067954. eCollection 2023. Front Aging Neurosci. 2023. PMID: 36819716 Free PMC article.

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Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

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Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

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