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Clinical Trial
. 2019 Apr 17;6(5):932-944.
doi: 10.1002/acn3.779. eCollection 2019 May.

Neurofilament as a potential biomarker for spinal muscular atrophy

Basil T Darras  1 , Thomas O Crawford  2   3 , Richard S Finkel  4 , Eugenio Mercuri  5 , Darryl C De Vivo  6 , Maryam Oskoui  7 , Eduardo F Tizzano  8 , Monique M Ryan  9 , Francesco Muntoni  10   11 , Guolin Zhao  12 , John Staropoli  12 , Alexander McCampbell  12 , Marco Petrillo  12 , Christopher Stebbins  12 , Stephanie Fradette  12 , Wildon Farwell  12 , Charlotte J Sumner  2   13
Affiliations
Clinical Trial

Neurofilament as a potential biomarker for spinal muscular atrophy

Basil T Darras et al. Ann Clin Transl Neurol. .

Abstract

Objective: To evaluate plasma phosphorylated neurofilament heavy chain (pNF-H) as a biomarker in spinal muscular atrophy (SMA).

Methods: Levels of pNF-H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease.

Results: Median pNF-H plasma level was 167.0 pg/mL (7.46-7,030; n = 34) in children without SMA (aged 7 weeks-18 years) and was higher in those aged < 1 versus 1-18 years (P = 0.0002). In ENDEAR participants with infantile-onset SMA, median baseline pNF-H level (15,400 pg/mL; 2390-50,100; n = 117) was ~10-fold higher than that of age-matched infants without SMA (P < 0.0001) and ~90-fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF-H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF-H levels: nusinersen-treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control-treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months.

Interpretation: Plasma pNF-H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF-H levels followed by relative stabilization. Together these data suggest plasma pNF-H is a promising marker of disease activity/treatment response in infants with SMA.

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Conflict of interest statement

This study was sponsored by Biogen (Cambridge, MA, USA). Biogen provided funding for medical writing support in the development of this paper; Rebecca Ayles, PhD, from Excel Scientific Solutions wrote the first draft of the manuscript based on input from authors, and Kristen DeYoung from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the paper to the authors. The authors had full editorial control of the paper and provided their final approval of all content. B.T.D. has been a member of advisory boards for AveXis, Biogen, Cytokinetics, PTC, Roche, Santhera, and Sarepta, with no financial interests in these companies; received research support from CureSMA, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the SMA Foundation, and Working on Walking Fund; and received grants from Biogen and Ionis Pharmaceuticals, Inc. during the ENDEAR, CHERISH, CS1/CS2, CS12, and CS11 studies, and from AveXis, Biogen, Cytokinetics, Fibrogen, PTC, Roche, Santhera, Sarepta, and Summit. T.O.C. has been an advisor/consultant for AveXis, Biogen, Catalyst, CureSMA, Cytokinetics, Marathon, Novartis, Roche, Sarepta, and the SMA Foundation. R.S.F. has received grants and advisor fees from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; received grants from Cytokinetics; been an advisor to AveXis, received grants for the STR1VE, STRONG and SPR1NT studies, and served on the data safety monitoring board for the AveXis AVX‐101 phase 1 gene transfer study; been an advisor to Novartis; been an advisor to Roche, received grants for the FIREFISH and SUNFISH studies, and served on the data safety monitoring board for the Moonfish phase 1b study; acted in an advisory capacity to nonprofit organizations: CureSMA, SMA Europe, the SMA Foundation, and SMA Reach (UK), outside the submitted work; and has received royalty payments from Children's Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. E.M. has been a member of advisory boards for SMA studies for AveXis, Biogen, Ionis Pharmaceuticals, Inc., Novartis, and Roche; been a principal investigator for ongoing Ionis Pharmaceuticals, Inc./Biogen, Novartis, and Roche clinical trials; received support from Biogen for a natural history registry; and received funding from Famiglie SMA Italy, Italian Telethon, and SMA Europe. D.C.D. has been an advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation, with no financial interests in these companies; and received grants/clinical trial support from Biogen, the Department of Defense, Hope for Children Research Foundation, Mallinckrodt, the National Institutes of Health, PTC, Sarepta, the SMA Foundation, and Ultragenyx. M.O. has been a member of advisory boards for Biogen; received grants from Biogen and Ionis Pharmaceuticals, Inc. during the ENDEAR, CHERISH, and CS11 studies, Cytokinetics, and Roche; and been a member of the data safety monitoring board for AveXis gene therapy studies. E.F.T. has received grant support to conduct clinical trials on SMA from Biogen and Ionis Pharmaceuticals, Inc.; serves as a consultant to AveXis, Biogen, Biologix, Cytokinetics, and Roche; and serves as a scientific/medical advisor to FAME Chile, Familias SMA Argentina, FUNDAME, SMA Europe, and TREAT‐NMD. He has received funding from Fundación Privada Daniel Bravo Andreu and SMA Europe. M.M.R. has received grants/advisor fees from Biogen, Genzyme, and Pfizer; been an advisor to and received funding from nonprofit organizations: FSHD Global Research Foundation, Muscular Dystrophy Association, Muscular Dystrophy Foundation, and Save Our Sons Duchenne Foundation. F.M. has been a member of advisory boards for AveXis, Biogen, Cytokinetics, Novartis, Pfizer, PTC, Roche, Sarepta, Summit, and Wave; been a principal investigator for ongoing Ionis Pharmaceuticals, Inc./Biogen and Roche clinical trials; and received funding from Muscular Dystrophy UK, SMA Europe, and SMA Trust UK. G.Z., J.S., A.M., M.P., C.S., S.F., and W.F. are employees of and hold stock/stock options in Biogen. J.S. reports a patent pending on behalf of Biogen. C.J.S. has received grant support from Ionis Pharmaceuticals, Inc.; and been a consultant for AveXis, Biogen, Pfizer, PTC, and Roche.

Figures

Figure 1
Figure 1
Plasma pNF‐H levels (single test per sample) in children without spinal muscular atrophy (A) by individual and (B) by age group. 7.46 pg/mL was used as the imputed value if the pNF‐H concentration was below the limit of quantification. The box represents the IQR and the whiskers the minimum and maximum values; the median is shown as a horizontal line within the box and the mean as a+. aThe highest value recorded in this group (395 pg/mL and designated by a dot) was considered an outlier by statistical analysis as it was greater than 1.5 × IQR. IQR = interquartile range; pNF‐H = phosphorylated neurofilament heavy chain.
Figure 2
Figure 2
(A) Mean plasma pNF‐H concentration (pg/mL) over time during the ENDEAR trial, and (B) percentage change from baseline in pNF‐H concentration (pg/mL) over time (nusinersen offset left for the purposes of graphic display). The results presented are statistical means and do not imply that the assay is capable of the sensitivity or precision necessary to generate results > 3 significant figures. pNF‐H = phosphorylated neurofilament heavy chain; SE = standard error.
Figure 3
Figure 3
Change in pNF‐H concentration for individual participants. (A) pNF‐H concentration (pg/mL) over time, and (B) percentage change from baseline in pNF‐H concentration (pg/mL) over time. pNF‐H values are presented for study visits that the individual attended and provided a blood sample. pNF‐H = phosphorylated neurofilament heavy chain.
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