Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes Megan A

Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes Megan A. Waldrop, MD,a,b Cassandra Karingada, MSN,c Mike A. Storey, PharmD, PharmD,d Brenna Powers, DPT,b Megan A. Iammarino, DPT,b Natalie F. Miller, DPT,b Lindsay N. Alfano, DPT,b Garey Noritz, MD,e Ian Rossman, MD PhD,f Matthew Ginsberg, MD,f Kathryn A. Mosher, MD,g Eileen Broomall, MD,h Jessica Goldstein, MD,i Nancy Bass, MD,i Linda P. Lowes, PhD,b Chang-Yong Tsao, MD,a,c Jerry R. Mendell, MD,a,b Anne M. Connolly, MDa,b

BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy abstract (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age ,2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age #8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1–23 months) treated in the state of Ohio. RESULTS: In children #6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with g glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and g glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post–gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

Departments of aNeurology and Pediatrics, The Ohio State University, Columbus, Ohio; bCenter for Gene Therapy WHAT’S KNOWN ON THIS SUBJECT: Spinal muscular and cDepartments of Neurology and dPharmacy, Nationwide Children’s Hospital, Columbus, Ohio; eDepartment of atrophy is an inherited neurodegenerative Pediatrics, Nationwide Children’s Hospital and The Ohio State University, Columbus, Ohio; fDepartments of neuromuscular disease. There are now two safe and g ’ h Pediatric Neurology and Pediatric Physiatry, Akron Childrens Hospital, Akron, Ohio; Department of Pediatric highly effective Food and Drug ’ i Neurology, Cincinnati Childrens Hospital, Cincinnati, Ohio; and Division of Pediatric Neurology, Department of – Pediatrics, Rainbow Babies and Children’s Hospital, Cleveland, Ohio Administration approved genetic therapies. However, the Food and Drug Administration indications were Drs Waldrop and Connolly conceptualized and designed the study, drafted the initial manuscript, much broader than those assessed in clinical trials. conducted initial data analyses, and reviewed and revised the manuscript; Ms Karingada, Ms Powers, Dr Iammarino, Ms Miller, and Drs Alfano, Drs Noritz, Rossman, Ginsberg, Mosher, Broomall, WHAT THIS STUDY ADDS: In this retrospective review, Goldstein, Bass, Lowes, and Tsao coordinated and supervised data collection and critically reviewed we report the safety and early efﬁcacy of the manuscript; Dr Mendell conducted data analysis and critically reviewed the manuscript for onasemnogene abeparvovec-xioi in all spinal muscular important intellectual content; and all authors approved the ﬁnal manuscript as submitted. atrophy patients aged ,2 years within Ohio DOI: https://doi.org/10.1542/peds.2020-0729 regardless of phenotype. Accepted for publication Jun 19, 2020 To cite: Waldrop MA, Karingada C, Storey MA, et al. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics. 2020;146(3):e20200729

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 146, number 3, September 2020:e20200729 ARTICLE 5q-linked spinal muscular atrophy approved product) between insert, Biogen), and was noted to have (SMA) is an autosomal recessive December 2018 and February 2020 a concurrent parainfluenza 3 degenerative neuromuscular disease and who have completed the infection. Subsequent candidates caused by the absence of the SMN1 prednisolone course for were required to wait 3 months after gene and insufficient survival motor immunosuppression. last nusinersen dosing before neuron protein.1,2 Both severity of receiving gene therapy. On the basis disease and age of onset are predicted of this occurrence, we believe there is by the copy number of a second gene, METHODS a theoretical risk of SMN2 , which is also inherited in an Children were included from four thrombocytopenia and potentially 3 autosomal recessive fashion. In its children’s hospitals in Ohio: other unknown complications when most common and severe form, type Nationwide Children’s Hospital, switching from nusinersen to 1, children either die or are Rainbow Babies and Children’s onasemnogene abeparvovec-xioi and dependent on mechanical ventilation Hospital, Cincinnati Children’s believed a longer waiting time 1,4 by 2 years of age. However, the Hospital, and Akron Children’s between last dose of nusinersen and approval of 2 therapies since late Hospital. All individuals were the switch may minimize this risk. 2016 has markedly changed the approved for inclusion in this report Children could not be ill at the time of 5,6 course of this disease. by each institution’s Institutional gene transfer. One child recovering from an acute illness was treated as One of these therapies uses an adeno- Review Board. Anyone who received an inpatient. If a child had been ill associated virus serotype 9 (AAV9) either AVXS-101 through the before gene transfer, at least 9 days vector to replace the missing SMN1 managed access program or were required from resolution of gene. Researchers of initial studies in onasemnogene abeparvovec-xioi illness before dosing. At that time, murine models demonstrated SMN commercially and completed their repeat laboratory values, including protein expression in motor neurons prednisolone course and taper by AAV9 antibodies, were obtained and and peripheral tissues and an April 30, 2020, were included. – were normal before proceeding with extended life span.7 10 Researchers of Children were identified in two ways. dosing. Prednisolone (1 mg/kg per additional studies in a porcine model The first group was presymptomatic day) was started the day before gene showed similar efficacy.11 After the and discovered after confirmation of transfer to suppress response to the successful SMA phenotype reversal in a positive newborn screen result (n = AAV.6 Children were dosed either as these models, a human trial in 15 5). The second genetically confirmed “outpatient in a bed” or the infusion children with type 1 SMA ,8 months group were symptomatic children center and were discharged ∼4 hours of age demonstrated safety and without end-stage disease (n = 16). after the infusion (except for one efficacy.6 Subsequently, SMN1 gene To determine eligibility for treatment, child who was treated while replacement therapy, onasemnogene every child who met the Food and inpatient). Follow-up laboratory abeparvovec-xioi, was Food and Drug Drug Administration criteria had studies included platelets, aspartate Administration approved on May 24, screening laboratory studies done, aminotransferase (AST), alanine 2019, for any patient age ,2 years including complete blood count with aminotransferase (ALT), GGT, without end-stage disease. Thus, the platelets, comprehensive metabolic prothrombin, bilirubin, and troponin I safety and important features of drug panel, g glutamyl transpeptidase and were obtained weekly for $4 administration in older (and likely (GGT), prothrombin, troponin I, HIV, weeks. If at any point the AST, ALT, or heavier) individuals has not been well hepatitis B and C screening, and AAV9 GGT increased to .2 times normal, studied or reported. antibody status (,1:50 required). If the prednisolone dose was increased In this article, we review the Ohio the results of the above studies were to 2 mg/kg per day. No child required experience of treating an additional within normal range, children were an increase beyond 2 mg/kg per day 21 children with a mean age of 10 6 eligible for treatment. An additional prednisolone dosing. Although the 7 months. We provide key safety stipulation at Nationwide Children’s AST, ALT, and GGT did continue to laboratory values and early outcomes Hospital was implemented after one rise in some children, the absence of for all individuals who have been managed access patient developed an increase in bilirubin, prothrombin dosed after the original research trial. clinically significant time, or symptoms led to the decision These include children who received thrombocytopenia (platelets ,50 to keep the dose at 2 mg/kg per day AVXS-101 gene transfer via a free K/µL) on day 7 after gene transfer. in these children. The 2 mg/kg per managed and expanded access This child had received gene transfer day dose was maintained until the program (before commercial 1 month after a nusinersen dose, an transaminases returned to ∼2 times approval) or onasemnogene antisense oligonucleotide with known the upper limit of normal and was abeparvovec-xioi (commercially potential to lower platelets (package then decreased slowly while close

Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 WALDROP et al TABLE 1 Summary of Important Clinical and Safety Data in All Treated Children Patient Age at Wt at SMN2 Nusinersen Platelets Day 7 AST Peak ALT Peak GGT Peak Fever on No. Weeks on “Full Infusion, mo Infusion, kg Copy No. Previously? (nl ,60) (nl ,50) (nl ,78) Day 3–4 Steroid Dose” 1a 1 4.2 2 No 154 62 36 — No 4 2a 2 5.4 3 No — 53 53 20 No 6 3a 3 4.8 3 No 186 92 79 38 No 4 4 4 6.5 2 No 179 124 67 23 Yes 4 5 4 5.1 2 No 234 507 469 201 Yes 11 6 4.5 5.9 2 Yes 384 53 40 20 No 6 7 5 6.5 2 No 297 129 96 58 No 4 8a 5 9.2 4 No 204 144 89 13 No 4 9a 6 8.8 4 Yes 219 172 192 62 Yes 11 10 8 7.5 2 Yes 33 339 228 111 Yes 10.5 11 8 7.9 2 Yes 65 122 62 17 Yes 4 12 8 8.1 2 No 171 807 1187 251 No 14 13 10 9.7 3 No 146 118 113 21 Yes 6 14 11 10 2 Yes 129 83 54 18 No 4 15 12 8.2 3 No 559b 1471 1794 163 Yes 10 16 17 11 2 Yes 108 116 108 26 Yes 4 17 17 8.2 3 Yes 142 177 212 13 No 8 18 19 12 3 Yes 127 1040 1137 83 Yes 10 19 22 8.0 3 Yes 110 1953 1935 376 No 13.5 20 23 10.9 2 Yes 182 66 47 15 No 7 21 23 11.7 2 Yes 52 1114 1002 240 No 11 —, not applicable. a Denotes those identiﬁed via newborn screening. b Denotes the child who did not have a decline in platelets. Patient 1 did not have GGT checked. Patient 2 was not able to obtain laboratories on day 7. clinical and laboratory monitoring SMN2 copy number, previous and the remaining 17 were dosed continued. nusinersen use, laboratory values, commercially (3 sites). Seven of the 9 and prednisone course. One patient children who were #6 months of age was dosed under a single-patient had no noteworthy elevation in AST, RESULTS Investigational New Drug application, ALT, or GGT (Figs 1–3) after gene Twenty-one children are included in 3 patients were dosed via the transfer. Five of these children were Table 1, providing age at treatment, managed access program (2 sites), identiﬁed from newborn screening

FIGURE 1 AST values over time (baseline to several weeks after gene delivery). On the left, children who were identiﬁed and treated before symptoms are represented. In the middle, symptomatic children who were treatment naive before gene transfer are represented. On the right, children who transitioned from nusinersen to onasemnogene abeparvovec-xioi are represented. Patient 9 is represented in both the left and right graphs (both identiﬁed off newborn screen and treated after receiving nusinersen).

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 146, number 3, September 2020 3 FIGURE 2 ALT values over time (baseline to several weeks after gene delivery). On the left, children who were identified and treated before symptoms are represented. In the middle, symptomatic children who were treatment naive before gene transfer are represented. On the right, children who transitioned from nusinersen to onasemnogene abeparvovec-xioi are represented. Patient 9 is represented in both the left and right graphs (both identified off newborn screen and treated after receiving nusinersen). and were considered child had difficulty taking 6 months of age or younger with presymptomatic. Two of these 5 prednisolone and better tolerated the ability to ensure appropriate children had elevations in AST and dissolvable prednisone tablets to prednisolone administration as the ALT with or without a concurrent maintain immunosuppression. The key safety factor. elevation in GGT. One had been second had noncompliance, with treated initially with nusinersen and abrupt discontinuations in In the older and heavier children, then transitioned to onasemnogene prednisolone dosing on two the liver impact as assessed by abeparvovec-xioi. In both cases, these occasions interrupting the needed transaminases was greater. Of the 12 elevations were related to suboptimal immunosuppression. Overall, gene children 8 months of age or older, 8 prednisolone administration. One transfer was well tolerated in those (67%) had elevations of $2 times the

FIGURE 3 GTT values over time (baseline to several weeks after gene delivery). On the left, children who were identiﬁed and treated before symptoms are represented. Of note, GGT was not checked in patient 1, so there are no data. In the middle, symptomatic children who were treatment naive before gene transfer are represented. Of note, patient 5 only had his GGT checked one time and was not included on the graph. On the right, children who transitioned from nusinersen to onasemnogene abeparvovec-xioi are represented. Patient 9 is represented in both the left and right graphs (both identiﬁed off newborn screen and treated after receiving nusinersen).

Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 WALDROP et al FIGURE 4 Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) values over time if available (baseline to a few months after gene delivery). On the left, children who were identified and treated before symptoms are represented. CHOP-INTEND was not completed on patient 1 and patient 9, so there are no data. In the middle, symptomatic children who were treatment naive before gene transfer are represented. CHOP-INTEND was not completed on patients 12 and 15, so there is no data. On the right, children who transitioned from nusinersen to onasemnogene abeparvovec-xioi are represented. CHOP-INTEND was not completed on patients 9, 18, and 21. Dashed line at 40 denotes level that is not reached in untreated SMA type 1 children.12 upper limit of normal in AST and/or had stabilization or improvement in Eight children were on bilevel ALT, and of these, 6 children also had functional outcomes. Seventeen positive airway pressure (BiPAP) at elevations in GGT .1 times normal. (89%) had objective improvements of night before gene transfer. After gene Of the 12 children who weighed $8 at least 1 point in functional outcome transfer, 7 remain on BiPAP, 1 has kg, 10 (83%) had elevations of scores by 4 months (Fig 4, Table 2). transitioned to intermittent use only $2 times the upper limit of normal in Twelve of these (70%) demonstrated when ill or after a particularly tiring AST and/or ALT, and of these, 4 a $3 point improvement by 4 months day, and 1 child no longer requires children also had elevations in GGT (mean: 8.1 6 4.7, range: 3–20 points). BiPAP. One child, as noted above, was .1 times normal. However, all not receiving any breathing support patients remained clinically well and Sixteen of the 17 children who were before gene transfer but required had no abnormalities indicative of feeding orally before gene transfer ventilator support after gene transfer symptomatic liver dysfunction (data maintained this ability after gene because of a severe respiratory not shown). transfer. One child with SMA type 1, illness. dosed at age 5 months, was Regardless of age or weight, a decline symptomatic before treatment and in platelet count was present in CONCLUSIONS developed a significant respiratory nearly all patients at the time of the illness 2 weeks after gene transfer. Onasemnogene abeparvovec-xioi was first posttransfer laboratory She subsequently required well tolerated in all children treated assessment (day 7 after gene a tracheostomy and gastric feeding in the state of Ohio. Our experience transfer). Nineteen children (90%) tube. Another 2 children with SMA, suggests that when a thorough had a decline in platelet count on day dosed at age 4.5 and 8 months, were screening process is completed, social 7 after gene transfer, with 73% (n = unable to feed by mouth before gene isolation is implemented to minimize 14) ,200 K/µL and 16% (n =3) transfer and are now able to take the risk of illness after gene transfer, ,100 K/µL. None were symptomatic some purees by mouth. Of the 4 and patients are monitored closely in or required treatment and all children who were feeding partially the weeks to months after gene returned to a value of $150 K/µLby by mouth before gene transfer, all transfer, adverse events are few. We day 14, and subsequent platelet have been able to continue to make do recommend delaying gene transfer counts remained normal. progress in oral feeding since gene until complete resolution of Nineteen children completed at least transfer, but none are able to preexisting viral illnesses. We also two functional assessments, and all exclusively feed orally at this time. recommend a delay in live

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 146, number 3, September 2020 5 TABLE 2 Summary of Functional Data in all Treated Children Patient CHOP CHOP 1 mo CHOP 2 mo CHOP 3 mo CHOP 4 mo Sitting Sitting Oral Feeding Oral Feeding BiPAP Before? BiPAP After? Baseline, After After After After Before? After? Before? After? Unless Speciﬁed 1a —————N/A Yes Yes Yes No No 2a 51 — 56 ——N/A Yes Yes Yes No No 3a 62 64 ———N/A Yes Yes Yes No No 4252929——N/A No Yes Yes No No 522———26 N/A No No No Yes Yes 628283548— N/A Yes No Yes, partial Yes, night No 725——25 — N/A No Yes No No Yes, vent 8a 62 — 64 ——N/A Yes Yes Yes No No 9a 24 Bayley — 33 Bayley ——Yes Yes Yes Yes No No 10 26 34 — 38 — No Yes No Yes, partial Yes, night Yes, intermittent 11 51 62 59 ——No Yes Yes, partial Yes, partial Yes, Yes, intermittent intermittent 12 36 HINE, 6 — 35 ——No No Yes Yes Yes, night Yes, night AIMS 13 44 47 49 ——Yes Yes Yes Yes No No 14 38 47 48 ——No No No No Yes, night Yes, night 15 28 Bayley 28 Bayley 28 Bayley 28 Bayley — Yes Yes Yes Yes No No 16 34 42 ———No No Yes, partial Yes, partial Yes, night Yes, night 17 43 — 46 ——Yes Yes ———— 18 15 HFMSE 15 HFMSE 16 HFMSE ——Yes Yes Yes, partial Yes, partial No No 19 49 51 49 50 — No No Yes Yes Yes, night Yes, night 20 52 52 52 54 — Yes Yes Yes, partial Yes, partial Yes, night Yes, night 21 9 RHS 15 RHS 15 RHS 18 RHS — Yes Yes Yes Yes No No Note: some children did not have the Children’s Hospital of Philadelphia (CHOP) Infant Test of Neuromuscular Disorders completed, and for those children, the outcome measure used is listed. Because of the retrospective and multisite nature of this review, this was unavoidable, and outcome measures are listed as obtained. AIMS, Alberta Infant Motor Scale; Bayley, Bayley Scales of Infant and Toddler Development, Third Edition, Gross Motor Subtest raw score; HFMSE, Hammersmith Functional Motor Score Expanded; HINE, Hammersmith Infant Neurological Examination; N/A, not applicable; RHS, Revised Hammersmith Score; —, value not obtained. a Denotes those identiﬁed off newborn screening.

vaccinations until 4 weeks after the prednisolone course were in the older the basis of preclinical studies,13 prednisolone course and taper have age group, usually .8 months and/or regardless of patient age or weight at been completed. .8 kg. These children had AST and dosing. In this Ohio population, there were no ALT elevations with or without Interestingly, almost all children had clinically significant adverse events increases in GGT. The transaminase a drop in platelet count on day 7 after after gene transfer. However, just over elevation may be due to total viral gene transfer. This is likely half of our patients required load received, as would be complement mediated given the a prolonged prednisolone course encountered in larger patients. timing. Only one child had a clinically compared with none of the 15 However, as there were some children apparent concomitant viral infection. fi children in the phase 1 study.6 In in this group without signi cant All of the children (n = 3) with children #6 months of age, the key to elevations, it may also be related to a platelet drop below 50 K/µL had successful post–gene transfer clinical differing immune responses to AAV9. been transitioned from nusinersen course is dependent on prednisolone We conclude that regular post–gene therapy. However, platelet count administration. These young children transfer laboratory monitoring and drops did also occur in nusinersen- are often still feeding by mouth and clinical assessments are critical while naive children, suggesting that may resist taking this medication. taking prednisolone and until the nusinersen is not the sole Care must be taken to ensure that the course has been completed. It is also contributing factor but may confer prescribed dosage is received and important to point out that all greater risk for a more significant given properly, with flexibility in immune responses to AAV were decline. Nevertheless, no child had delivery method (oral liquid, crushed controlled with prednisolone alone any clinical symptoms of tablets, dissolvable tablets) as and did not require more aggressive thrombocytopenia, nor required required. The majority of children immune suppression thought additional treatment, and all platelet who required a prolonged necessary by some investigators on count normalized on day 14. All

Downloaded from www.aappublications.org/news by guest on October 2, 2021 6 WALDROP et al children should be monitored closely and objective testing by physical these are promising results for for thrombocytopenia after gene therapists showed that 89% have single-dose gene delivery with transfer, and extra consideration had improvements in their onasemnogene abeparvovec-xioi in should be given for a child outcome measures. Because of infants 1 to 23 months of age. with lower platelets before gene the heterogeneous ages and transfer. baseline functional testing at ABBREVIATIONS Finally, all symptomatic individuals infusion we cannot comment on the experienced subjective and objective effect of age at dosing on expected AAV9: adeno-associated virus functional improvements in motor improvement. We can, however, state serotype 9 function. In the 5 children treated that functional improvements were ALT: alanine aminotransferase before symptoms, no signs of measured across the cohort AST: aspartate aminotransferase weakness characteristic of SMA regardless of age at infusion and BiPAP: bilevel positive airway have developed over follow-up previous treatment status. These data pressure periods of 2 to 8 months. Parents are currently limited because of GGT: g glutamyl transpeptidase consistently reported improvements variations in functional assessments SMA: spinal muscular atrophy in motor skills for their children and length of follow-up. However,

Address correspondence to Megan A. Waldrop, Center for Gene Therapy, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Waldrop has served on advisory boards for Sarepta Therapeutics and Avexis Inc. Dr Storey has served on advisory boards for Avexis Inc and Sarepta Therapeutics. Dr Mendell has received personal fees from Sarepta Therapeutics, Avexis Inc, and Vertex Pharmaceuticals. Dr Connolly has served on advisory boards for Sarepta Therapeutics, Avexis, and Genentech-Roche and serves on the Data and Safety Monitoring Board for Catabasis; the other authors have indicated they have no ﬁnancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: Dr Waldrop has served on advisory boards for Sarepta Therapeutics and Avexis Inc. Dr Storey has served on advisory boards for Avexis Inc and Sarepta Therapeutics. Dr Mosher has served on advisory boards for Sarepta and PTC Therapeutics. Drs Goldstein and Bass have served on speaker and advisory boards for Biogen. Dr Alfano has served on advisory boards for Genentech-Roche, Acceleron Pharma, and Audentes Therapeutics. Dr Mendell has received personal fees from Sarepta Therapeutics, Avexis Inc, and Vertex Pharmaceuticals. Dr Connolly has served on advisory boards for Sarepta Therapeutics, Avexis, and Genentech-Roche and serves on the DMSB for Catabasis; the other authors have indicated they have no potential conﬂicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes Megan A. Waldrop, Cassandra Karingada, Mike A. Storey, Brenna Powers, Megan A. Iammarino, Natalie F. Miller, Lindsay N. Alfano, Garey Noritz, Ian Rossman, Matthew Ginsberg, Kathryn A. Mosher, Eileen Broomall, Jessica Goldstein, Nancy Bass, Linda P. Lowes, Chang-Yong Tsao, Jerry R. Mendell and Anne M. Connolly Pediatrics originally published online August 25, 2020;

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