Mercuri, Eugenio

Muntoni, Francesco

Servais, Laurent

Straub, Volker

English

UCL Discovery

Journal of Neuromuscular Diseases 10 (2023) 1151–1153DOI 10.3233/JND-239004IOS Press1151Letter to the EditorLetter to the Editor: In response to P.R.Clemens et al., Efficacy and Safety ofViltolarsen in Boys with DuchenneMuscular Dystrophy: Results From thePhase 2, Open-Label, 4-Year ExtensionStudy, and Long-Term Functional Efficacyand Safety of Viltolarsen in Patients withDuchenne Muscular DystrophyFrancesco Muntonia, Volker Straubb, Laurent Servaisc and Eugenio MercuridaDubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond StreetInstitute of Child Health & Great Ormond Street Hospital for Children Foundation Trust, London, UKbInstitute of Genetic Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, UKcDepartment of Pediatrics, University of Oxford, Oxford, UKdPeadiatric Neurology, Catholic University, Rome, ItalyPublished 7 November 2023Dear Prof Bönnemann and Lochmüller,We are writing to express our concerns regardingseveral aspects of two recently published articles inthe Journal of Neuromuscular Diseases entitled:Clemens et al., Efficacy and Safety of Viltolarsenin Boys with Duchenne Muscular Dystrophy:Results From the Phase 2, Open-Label, 4-YearExtension Study [1]Clemens et al., Long-Term Functional Efficacy andSafety of Viltolarsen in Patients with Duchenne Mus-cular Dystrophy. [2]These 2 manuscripts are focused on aspects ofclinical efficacy of the chronic administration of Vil-tolarsen in a group of boys affected by Duchennemuscular dystrophy. Viltolarsen is an antisenseoligonucleotide designed to induce exon 53 skipping.As this was an open label study, an external clinicalcomparator, the CINRG cohort, was used to assessthe clinical benefit.For full disclosure, we are 4 academic PIs whorecently co-authored a series of manuscripts onanother morpholino antisense to induce exon 53 skip-ping (golodirsen). As academic investigators, wetruly welcome competing initiatives that bring newtherapies to people affected by DMD, and we arepleased to see that viltolarsen at the doses used(80 mg/kg) was on the whole well tolerated andclearly induced dystrophin protein expression. It isalso very good news for the field that viltolarsenISSN 2214-3599 © 2023 – The authors. Published by IOS Press. This is an Open Access article distributed under the termsof the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).1152 F. Muntoni et al. / Letter to the Editorreceived accelerated approval by FDA, increasingthe therapeutic options for people affected by DMD.We need, however, to draw your attention to severalinaccurate and potentially misleading statements pro-vided in these manuscripts that had not been identifiedduring the peer review process.CLAIMS OF CLINICAL EFFICACYIn these manuscripts there are serious shortcom-ings in the methodology used for comparing theclinical efficacy to the external controls.Already in the original JAMA Neurologymanuscript published in 2020 [3], where the earlyresults of the clinical trial were reported, there wereclaims of superiority of the treatment arm in compar-ison with historical controls at week 13. The datamatching conducted with the CINRG cohort wasimbalanced in relation to various clinical parameterspreviously demonstrated by several groups includ-ing CINRG investigators to play a crucial role ininfluencing disease trajectories.The imbalance between the treatment arm and theexternal CINRG arm is evident: the viltolarsen cohortfavorably compared to the CINRG cohort for time torun 10 meters, 6 minute walk test, time to climb 4steps, making the comparative analysis not robust. Inaddition, no information on the crucial corticosteroidexposure matching was provided.The two more recent manuscripts published by thesame authors in Journal of Neuromuscular Diseases[1, 2] use even less stringent propensity matchingcriteria between the treated patients and the exter-nal controls. Indeed, in these 2 studies, patients wereonly matched for age, weight, height and BMI, butnot for other crucial determinants of clinical severity,further diverging from the accepted methodologiesfor accurate and transparent clinical matching.The field has evolved considerably in the 8 yearsand several peer reviewed publications have clearlyidentified relevant factors for predicting trajectoriescompared to these simple demographic parameters[4-8]. In our opinion these omissions challenge there-fore the significance of the clinical reported findings.In our previous manuscript on exploratory clini-cal efficacy of golodirsen with a genotyped matchedexternal control [9], we used a stringent propen-sity score matching using age, corticosteroid usage,6MWT and rise from the floor, parameters that arewell recognized to have predictive value in DMD.While it is very likely that viltolarsen willeventually provide benefit to treated patients, theinappropriate propensity matching and the evolv-ing criteria used in different manuscripts weaken theclaim of superiority compared to golodirsen treatedpatients and complicates interpretation of the efficacyof the viltolarsen findings.CLAIMS OF SUPERIORITY IN THEPROTEIN PRODUCTION OF THEADMINISTRATION OF VILTOLARSENCOMPARED TO GOLODIRSENIn the discussion of the last paper in JNMD, theauthors state that “viltolarsen has shown a mean dys-trophin increase in muscle of 6%, whereas golodirsenadministration over 48 weeks resulted in dystrophinprotein being present at 1%”. However, this superi-ority claim lacks methodological robustness. Indeed,previous collaborative work including FDA regula-tors and senior authors of the viltolarsen manuscriptshad clearly indicated that it was not possible to per-form meaningful comparative analysis of westernblots performed in different labs as there is no dys-trophin standard carried over [10]. Furthermore, wealso note that the level of baseline dystrophin con-centration in the JAMA Neurology manuscript wasconsiderably higher compared to the one reported inthe original golodirsen manuscript [11]. Indeed, inthe 2 cohorts of the viltolarsen paper, the baselinedystrophin level was a mean of 0.3% in one of thetwo cohorts, and 0.6 in the second cohort.In the original golodirsen manuscript [11] the meanbaseline dystrophin level was 0.095% with only asingle patient having baseline protein levels above0.25%, which constitutes the lower limit of detection.The fold increase from baseline would if anythingappear to be more favourable for golodirsen com-pared to viltolarsen, but in view of the differences inmethodologies used in the different studies we feelmore prudent to conclude that both studies unequivo-cally demonstrated increased dystrophin production.We think that any comparison with the two productson the basis of these two studies can be misleading.In conclusion, this population of boys with DMDneeds efficacious therapeutic options and viltolarsenappears to provide and additional therapeuticopportunity. This is indeed very good news for thefield. However, the entire community needs findingsthat are reported and interpreted in an accurate andtransparent way. The discussion should avoid claimsF. Muntoni et al. / Letter to the Editor 1153of superiority that may provide them and/ or thecompany they represent with a commercial advan-tage, and journals should pay particular attentionfor this not to happen. Our patients and colleaguesdeserve balanced and robust evidence when decidingwhich therapies to use.Sincerely,Francesco MuntoniVolker StraubLaurent ServaisEugenio MercuriREFERENCES[1] Clemens PR, Rao VK, Connolly AM, Harper AD, MahJK, McDonald CM, Smith EC, Zaidman CM, NakagawaT; CINRG DNHS Investigators; Hoffman EP. Efficacy andSafety of Viltolarsen in Boys With Duchenne MuscularDystrophy: Results From the Phase 2, Open-Label, 4-YearExtension Study. J Neuromuscul Dis. 2023;10(3):439-47.[2] Clemens PR, Rao VK, Connolly AM, Harper AD, MahJK, McDonald CM, Smith EC, Zaidman CM, NakagawaT; CINRG DNHS Investigators; Hoffman EP. Long-TermFunctional Efficacy and Safety of Viltolarsen in Patientswith Duchenne Muscular Dystrophy. J Neuromuscul Dis.2022;9(4):493-501.[3] Clemens PR, Rao VK, Connolly AM, Harper AD, MahJK, Smith EC, McDonald CM, Zaidman CM, MorgenrothLP, Osaki H, Satou Y, Yamashita T, Hoffman EP; CINRGDNHS Investigators. Safety, Tolerability, and Efficacy ofViltolarsen in Boys With Duchenne Muscular DystrophyAmenable to Exon 53 Skipping: A Phase 2 RandomizedClinical Trial. JAMA Neurol. 2020;77(8):982-91.[4] Goemans N, Signorovitch J, Sajeev G, Yao Z, Gordish-Dressman H, McDonald CM, Vandenborne K, MillerD, Ward SJ, Mercuri E; investigators from PRO-DMD-01 Study, CINRG DNHS, ImagingDMD, and the DMDItalian Group. Suitability of external controls for drugevaluation in Duchenne muscular dystrophy. Neurology.2020;95(10):e1381-e1391.[5] Goemans N, Vanden Hauwe M, Signorovitch J, Swallow E,Song J; Collaborative Trajectory Analysis Project (cTAP).Individualized Prediction of Changes in 6-Minute WalkDistance for Patients with Duchenne Muscular Dystrophy.PLoS One. 2016;11(10):e0164684.[6] Muntoni F, Domingos J, Manzur AY, Mayhew A, GuglieriM; UK NorthStar Network; Sajeev G, Signorovitch J,Ward SJ. Categorising trajectories and individual itemchanges of the North Star Ambulatory Assessment inpatients with Duchenne muscular dystrophy. PLoS One.2019;14(9):e0221097.[7] Muntoni F, Signorovitch J, Sajeev G, Lane H, Jenkins M,Dieye I, Ward SJ, McDonald C, Goemans N, Niks EH,Wong B, Servais L, Straub V, Guglieri M, de Groot IJM,Chesshyre M, Tian C, Manzur AY, Mercuri E, Aartsma-RusA; Association Française Contre Les Myopathies; on behalfof Universitaire Ziekenhuizen Leuven Group, PRO-DMD-01, The UK NorthStar Clinical Network, CCHMC, and TheDMD Italian Group. DMD Genotypes and Motor Func-tion in Duchenne Muscular Dystrophy: A Multi-institutionMeta-analysis With Implications for Clinical Trials. Neu-rology. 2023;100(15):e1540-e1554.[8] Mercuri E, Signorovitch JE, Swallow E, Song J, WardSJ; DMD Italian Group; collaborative Trajectory AnalysisProject (cTAP).Neuromuscul Disord. 2017;27(5):e1.[9] Categorizing natural history trajectories of ambulatory func-tion measured by the 6-minute walk distance in patients withDuchenne muscular dystrophy” [Neuromuscular Disorders26/9 (2016) 576-583].[10] Servais L, Mercuri E, Straub V, Guglieri M, Seferian AM,Scoto M, Leone D, Koenig E, Khan N, Dugar A, WangX, Han B, Wang D, Muntoni F; SKIP-NMD Study Group.Long-Term Safety and Efficacy Data of Golodirsen inAmbulatory Patients with Duchenne Muscular DystrophyAmenable to Exon 53 Skipping: A First-in-human, Multi-center, Two-Part, Open-Label, Phase 1/2 Trial. Nucleic AcidTher. 2022;32(1):29-39.[11] Aartsma-Rus A, Morgan J, Lonkar P, Neubert H, OwensJ, Binks M, Montolio M, Phadke R, Datson N, VanDeutekom J, Morris GE, Rao VA, Hoffman EP, MuntoniF, Arechavala-Gomeza V; workshop participants. Reportof a TREAT-NMD/World Duchenne Organisation Meetingon Dystrophin Quantification Methodology. J NeuromusculDis. 2019;6(1):147-59. doi: 10.3233/JND-180357[12] Frank DE, Schnell FJ, Akana C, El-Husayni SH, DesjardinsCA, Morgan J, Charleston JS, Sardone V, Domingos J, Dick-son G, Straub V, Guglieri M, Mercuri E, Servais L, MuntoniF; SKIP-NMD Study Group. Increased dystrophin produc-tion with golodirsen in patients with Duchenne musculardystrophy. Neurology. 2020;94(21):e2270-e228[13] Reply to F. Muntoni et al.: “In response to P.R. Clemens et al,Efficacy and Safety of Viltolarsen in Boys with DuchenneMuscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study, and Long-Term FunctionalEfficacy and Safety of Viltolarsen in Patients with DuchenneMuscular Dystrophy. J Neuromuscul Dis. 2023;10(6):xx-xx

Letter to the Editor: In response to P.R. Clemens et al., Efficacy and Safety of Viltolarsen in Boys with Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study, and Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

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