Interim Efficacy and Safety Results from the Phase 2 NURTURE Study Evaluating Nusinersen in Presymptomatic Infants With Spinal Muscular Atrophy

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1 American Academy of Neurology th Annual Meeting April 22 28, 2017 Boston, MA Interim Efficacy and Safety Results from the Phase 2 NURTURE Study Evaluating Nusinersen in Presymptomatic Infants With Spinal Muscular Atrophy Darryl C. De Vivo, MD April 27, 2017 De Vivo DC, 1 Hwu W-L, 2 Reyna SP, 3 Farwell W, 3 Gheuens S, 3 Sun P, 3 Zhong ZJ, 3 Su J, 4 Schneider E, 4 Bertini E, 5 on behalf of the NURTURE Study Group 1 Department of Neurology, Columbia University Medical Center, New York, NY, USA; 2 Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; 3 Biogen, Cambridge, MA, USA; 4 Ionis Pharmaceuticals Inc., Carlsbad, CA, USA; 5 Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu Children s Research Hospital, Rome, Italy

2 Disclosures DCD: advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Roche, Sarepta, and the SMA Foundation, with no financial interests in these companies; grants from the Department of Defense, Hope for Children Research Foundation, the National Institutes of Health, and the SMA Foundation W-LH: advisor/consultant for Biogen; grants from Biogen SPR, WF, SG, PS, and ZJZ: employees of and hold stock/stock options in Biogen JS and ES: employees of and hold stock/stock options in Ionis Pharmaceuticals EB: advisor/consultant for AveXis, Biogen, Edison Pharmaceuticals, Novartis, and Roche; grants from Fondazione Telethon and the Italian Ministry of Health This study was sponsored by Biogen (Cambridge, MA, USA). Writing and editorial support for the preparation of this presentation was provided by Excel Scientific Solutions (Southport, CT, USA): funding was provided by Biogen

3 Introduction Spinal muscular atrophy (SMA) - Autosomal recessive neuromuscular disorder 1 - Caused by mutations in the SMN1 gene 1 - SMA Type I: onset by age 6 months, never rolls or sits independently 2 - SMA Type II: onset by age 6 18 months, sits, but never walks independently 2 Nusinersen - Antisense oligonucleotide 3 - Modifies splicing of the homologous SMN2 precursor mrna 3 - Leads to increased production of full-length SMN protein 3,4 NURTURE - Phase 2, open-label, multicenter, multinational, single-arm study - 12-mg scaled equivalent dose of intrathecal nusinersen - Infants with genetically diagnosed and presymptomatic SMA (most likely to develop Type I or II) - Previous interim analysis: Infants treated were achieving motor milestones generally consistent with normal development 5 in contrast to the natural history of SMA Type I 6 mrna = messenger RNA; SMN = survival of motor neuron. 1. Prior TW. Curr Opin Pediatr. 2010;22(6): Finkel R, et al; ENMC SMA Workshop Study Group. Neuromuscul Disord. 2015;25(7): Hua Y, et al. Genes Dev. 2010;24(15): Passini MA, et al. Sci Transl Med. 2011;3(72):72ra Bertini E, et al. Nusinersen in presymptomatic infants with spinal muscular atrophy (SMA): interim efficacy and safety results from the phase 2 NURTURE study. Presented at: 21st International Congress of the World Muscle Society; October 4-8, 2016; Granada, Spain. 6. Finkel RS, et al. Neurology. 2014;83(9):

4 Study Overview: Interim Analysis (Data Cut-off: October 31, 2016) Study schematic Efficacy set: 18 infants who have reached Day 64 or longer Nusinersen dosing Interim efficacy analysis period Infants completing visit Screening period ( 21 days) Dosing schedule Study day n=20 n=18 n=16 n=11 n=9 n=5 Nusinersen 12-mg scaled equivalent dose loading doses with follow-up evaluations Maintenance dose and follow-up evaluation every 119 days D868 post-treatment follow-up visit Participant disposition Key eligibility criteria: Age 6 weeks at first dose Presymptomatic SMA Genetic diagnosis of 5q SMA 2 or 3 SMN2 25 infants screened Identification Affected sibling, n=15 Newborn screening initiative, n=3 Prenatal screening, n=1 Known carrier status, n= 1 20 infants dosed 2 SMN2, n=13 3 SMN2, n=7 5 failed screening Discontinued treatment, n=0 Withdrawn from study, n=0 NURTURE study interim analysis data cut-off date: October 31, 2016.

5 Primary Endpoint: Time to Death or Respiratory Intervention a At the time of the interim analysis, infants had been enrolled for a median (range) ( ) days All infants were alive and none had required respiratory intervention Nusinersen-treated infants, n (%) 2 SMN2 n=13 3 SMN2 n=7 Total n=20 Alive 13 (100%) 7 (100%) 20 (100%) Required invasive ventilation or tracheostomy Required noninvasive ventilation for 6 hours/day continuously for 7 days NURTURE study interim analysis data cut-off date: October 31, a Respiratory intervention was defined as invasive or noninvasive ventilation for 6 hours/day continuously for 7 days or tracheostomy.

6 Infants, n Date of presentation: April 27, 2017 HINE Motor Milestone 1 Achievements a Motor function Full head control Independent sitting (stable sit, pivot [rotates]) Stands with support/ Stands unaided Total infants achieving, n Cruising/ Walking Expected age of attainment, mo a Infants achieving by expected age, n/n (%) 15/16 (94%) 10/12 (83%) 7/11 (64%) 5/9 (56%) Three of 9 infants 12 months of age had achieved standing unaided (expected age, 12 months) Two infants ~13 months of age had achieved independent walking (expected age, 15 months) 15 Did not achieve All the time upright Did not achieve Stable sit Pivot (rotates) Did not achieve Stands with support Stands unaided Did not achieve Cruising Walking independently Motor milestone achievement in interim efficacy set (n=18) a SMN2 (n=13) SMN2 (n=5) 6 2 SMN2 (n=13) 3 SMN2 (n=5) SMN2 (n=13) SMN2 (n=5) SMN2 (n=13) SMN2 (n=5) HINE = Hammersmith Infant Neurological Examination. a Among 18 Infants With Day 64 Assessment. NURTURE study interim analysis data cut-off date: October 31, a In healthy infants. 1. Haataja L, et al. J Pediatr. 1999;135(2 pt 1):

7 Growth Parameters: Efficacy Set Date of presentation: April 27, 2017 All but 1 infant gained weight over time; every infant s weight was higher at the last observation vs. baseline At Day 183, 4/16 (25%) infants met the criteria for growth failure - 1 infant (2 SMN2 ) had a percutaneous gastric tube inserted at Day 155 to assist with feeding - All infants stabilized on a new growth curve and continued to grow over time At Day 365: - Three of 9 (33%) infants met the criteria for growth failure - Four of 9 (44%) had protocol-defined symptoms of SMA a All 4 infants were sitting without support and 1 infant was standing with assistance All continued to gain weight over time Growth failure: Weight for age below the 5 th percentile (WHO growth charts) or weight for age failing 2 major percentiles over a 6-month period. Relevant protocol-defined symptoms of SMA: Weight for age below 5 th percentile Weight for age decreased 2 major percentiles vs. baseline Failure to demonstrate all expected WHO motor milestones NURTURE study interim analysis data cut-off date: October 31, a Three infants had weight for age below the fifth percentile, a decrease of 2 major percentiles in weight for age, and did not achieve expected WHO motor milestones by 13 months of age, and 1 infant did not achieve expected WHO motor milestones by 13 months of age.

8 Summary of Safety The lumbar puncture procedure was generally well tolerated There were no clinically significant adverse changes in laboratory or neurological examinations considered related to nusinersen All AEs considered by the investigator to be possibly related to study drug resolved during study follow-up AE, n (%) Total n=20 Any AE 16 (80%) SAE a 6 (30%) Severe AE 2 (10%) AE related to study drug b 0 AE possibly related to study drug b 3 (15%) Muscular weakness and weight-bearing difficulty 1 (5%) Hyperreflexia and tachycardia 1 (5%) Pyrexia, increased ALT, increased AST with increased eosinophil count, lymphocyte count, and WBC count 1 (5%) SAE related to study drug 0 AE leading to treatment discontinuation or withdrawal 0 AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SAE = serious adverse event; WBC = white blood cell. NURTURE study interim analysis data cut-off date: October 31, a SAEs were bronchitis, choking, and pneumonia (n=1); pneumonia (n=1); urinary tract (n=1); failure to thrive (n=1); pyrexia (n=1); and abdominal distension, respiratory distress, dehydration, and rhinovirus infection (n=1). b Assessed by the investigator.

9 Conclusions These results from the second interim analysis of NURTURE extend those from a June 2016 interim analysis - Continued beneficial effects of nusinersen in infants with presymptomatic SMA on survival and achievement of motor milestones over the expected natural history of SMA Type I 1 - All infants are alive without requiring chronic respiratory support and are exhibiting improvements in motor function and/or motor milestones - Most infants are achieving motor milestone and growth parameter gains generally consistent with normal development - Achievement of motor milestones not acquired by infants with SMA Type I or II Nusinersen was well tolerated and no specific safety concerns were identified NURTURE study interim analysis data cut-off date: October 31, Finkel RS, et al. Neurology. 2014;83(9):

10 Acknowledgments The authors thank the patients who are participating in this study and their parents/guardians and family members, without whom this effort cannot succeed The authors also thank the people who are contributing to this study, including the study site principal investigators, clinical monitors, study coordinators, physical therapists, and laboratory technicians

11 Back up

12 Baseline Characteristics Characteristic Age at first dose, d, n (%) 2 SMN2 3 SMN2 n=13 a n= (46) 2 (29) 8 (40) >14 to 28 5 (38) 3 (43) 8 (40) >28 2 (15) 2 (29) 4 (20) Median (range) 15.0 (3 41) 24.0 (10 42) 19.0 (3 42) Male, n (%) 8 (62) 3 (43) 11 (55) Female, n (%) 5 (38) 4 (57) 9 (45) Region, n (%) North America 7 (54) 6 (86) 13 (65) Europe 4 (31) 0 4 (20) Asia-Pacific 2 (15) 1 (14) 3 (15) Mean CHOP INTEND total score Median (range; n) b ( ; 13) Mean HINE total motor milestones Median (range; n) b (0 5.0; 13) Mean ulnar CMAP amplitude Median (range; n), mv b ( ; 13) Mean peroneal CMAP amplitude Median (range; n), mv b ( ; 10) ( ; 5) ( ; 5) ( ; 5) ( ; 5) Total n= ( ; 18) (0 7.0; 18) ( ; 18) ( ; 15) NURTURE study interim analysis data cut-off date: October 21, a Included 1 set of twins each with 2 of SMN2. b Based on efficacy set of patients who completed Day 64 visit or longer (n=18).

13 Change in HINE Motor Milestone Scores Across Studies NURTURE (N=18) ENDEAR (CS3B)-nusinersen (N=73) CS3A (N=20) ENDEAR (CS3B)-control (N=37) Mean (SE) total milestone score a NURTURE CS3A CS3B-nusinersen CS3B-control Scheduled visit day NURTURE (presymptomatic infantile-onset SMA; 2 or 3 SMN2 ) b (11/2016 data cut) CS3A (infantile-onset SMA) c (1/2016 data cut) Nusinsersen vs. Sham procedure control in ENDEAR final analysis (infantile-onset SMA; 2 SMN2 ) d Populations: NURTURE (232SM201) = interim efficacy set, CS3A = all dosed infants; ENDEAR (CS3B) = interim efficacy set. For each study, visits with n<5 are not plotted. a Maximum total milestone score = 26. b Median (range) age at first dose: 19.0 (8 42) days. c Median (range) age at enrollment: 155 (36 210) days. d Median (range) age at first dose: (30 262) days.

14 Growth Parameters: Efficacy Set Date of presentation: April 27, 2017 All but 1 infant gained weight over time; each infant s weight was higher at the last observation vs. baseline Four of 16 (25%) infants met the criteria for growth failure a at Day infant (2 SMN2 ) had a percutaneous gastric tube inserted to assist with feeding - All infants stabilized on a new growth curve and continued to grow over time Three of 9 (33%) infants met the criteria for growth failure a and 4/9 (44%) had protocol-defined symptoms of SMA b at Day All 4 infants were sitting without support and 1 infant was standing with assistance at Day 365; all continued to gain weight over time Baseline n=18 Day 183 n=16 Day 365 n=9 Parameter, n (%) 2 SMN2 n=13 3 SMN2 n=5 2 SMN2 n=11 3 SMN2 n=5 2 SMN2 n=6 3 SMN2 n=3 Weight for age below fifth percentile 1 (8%) 0 Growth failure a 3 (27%) 1 (20%) 4 (67%) 0 Weight for age decreased by 2 major percentiles 3 (27%) 1 (20%) 3 (50%) 0 Weight-for-age below fifth percentile 2 (18%) 0 3 (50%) 0 Protocol-defined symptoms of SMA b 4 (67%) 0 NURTURE study interim analysis data cut-off date: October 31, a Growth failure was defined as weight for age below the fifth percentile (based on World Health Organization [WHO] growth charts) or a decreased growth velocity resulting in weight for age failing 2 major percentiles over a 6-month period. b Three infants had weight for age below the fifth percentile, a decrease of 2 major percentiles in weight for age, and did not achieve expected WHO motor milestones by 13 months of age, and 1 infant did not achieve expected WHO motor milestones by 13 months of age.

15 Modified Section 2 of the HINE Scoring and Normal Age of Achievement a Motor function Milestone progression score Voluntary grasp No grasp Uses whole hand Index finger and thumb but immature grasp Ability to kick (supine) Head control No kicking Unable to maintain upright; <3 mo Kick horizontal, legs do not lift Wobbles; 4 mo Upward (vertical); 3 mo All the time upright; 5 mo Rolling No rolling Rolling to side; 4 mo Prone to supine; 6 mo Sitting Cannot sit Sit with support at hips; 4 mo Pincer grasp Touches leg; 4 5 mo Supine to prone; 7 mo Touches toes; 5 6 mo Props; 6 mo Stable sit; 7 mo Pivots (rotates); 10 mo Crawling Does not lift head On elbow; 3 months On outstretched hand; 4 5 mo Standing Does not support weight Supports weight; 4 5 mo Stands with support; 8 mo Walking No walking Bouncing; 6 mo Cruising (walks holding on); 11 mo Crawling flat on abdomen; 8 mo Stands unaided; 12 mo Walking independently; 15 mo On hands and knees; 10 mo Overall maximum total score = 26 (higher score indicates milestone attained) Haataja L, et al. J Pediatr. 1999;135(2 pt 1): a Ages (months) are considered to be the normal age of achievement in individuals without SMA.

16 Study Endpoints Primary - Time to respiratory intervention (invasive or noninvasive ventilation for 6 hours/day continuously for 7 days or tracheostomy) or death Secondary - Safety, tolerability, and pharmacokinetics - Effect on development of SMA by assessing clinical milestones Ability to sit, crawl, stand, or walk - Motor function milestones Assessed using CHOP INTEND, 1 HINE, 2 and WHO 3 - Survival (proportion of patients alive) - Growth parameters CHOP INTEND = Children s Hospital of Philadelphia Infant Test of Neuromuscular Disorders. 1. Haataja L, et al. J Pediatr. 1999;135(2 pt 1): WHO Multicentre Growth Reference Study Group. Acta Paediatr Suppl. 2006;450: Glanzman AM, et al. Neuromuscul Disord. 2010;20(3):

17 Mean (SE) HINE total motor milestone score Mean HINE Total Motor Milestone Score Over Time Date of presentation: April 27, 2017 In general, all enrolled infants demonstrated increased motor milestone scores from baseline to last evaluation - Seventeen (94%) infants achieved improvement HINE motor milestones a at the last visit - Milestone gain followed a similar trajectory for infants with 2 and 3 of the SMN2 gene - Loss of HINE motor milestones was infrequent and often transient - Maximal total score on HINE is 26 points by 15 months of age 2 SMN2, n 3 SMN2, n Total, n Study visit day SMN2 3 SMN2 Total 5 5 Maximum total score, 26 points NURTURE study interim analysis data cut-off date: October 31, a Achievement in any of the HINE motor milestone categories in which there were more categories with improvement than worsening.

18 Mean (SE) CHOP INTEND total score Date of presentation: April 27, 2017 Mean CHOP INTEND Total Score Over Time Baseline median (range) CHOP INTEND total score was 54.0 ( ) points in the total efficacy population - CHOP INTEND total scores in infants with SMA who were 6 months of age and had 2 of SMN2 gene from a natural history study ranged from points 1 Sixteen (89%) infants achieved an 4-point improvement One (6%) infant had an 4-point decrease Seven (39%) achieved the maximum total score (64 points) 6 5 Maximum total score, 64 points SMN2, n 3 SMN2, n Total, n Study visit day SMN2 3 SMN2 Total NURTURE study interim analysis data cut-off date: October 31, Kolb SJ, et al; NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators. Ann Clin Transl Neurol. 2016;3(2):