NEW HORIZONS IN TREATING SMA. Dr. Huda Mussaffi Schneider Children s Medical Center of Israel

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1 NEW HORIZONS IN TREATING SMA Dr. Huda Mussaffi Schneider Children s Medical Center of Israel

2 WHAT IS SMA? Rare and debilitating autosomal recessive neuromuscular disease characterized by degeneration of motor neurons of the spinal cord Severe and progressive muscle atrophy and weakness Leading monogenetic cause of infant and childhood mortality Five subtypes of SMA have been described SMA, spinal muscular atrophy. Lunn MR & Wang CH. Lancet. 2008;371: ; Prior TW & Russman BS. GeneReviews. Accessed Mar 2016; Monani UR, et al. Hum Mol Genet. 2000;9:

3 SMA DISEASE CLASSIFICATION International SMA Consortium (ISMAC) system Based on age of onset and maximum motor function achieved 1 Types of SMA 1-3 SMA type Age of onset Motor function achieved Type 0 a Prenatal None Type I 0 6 months Sit with support only Type II 7 18 months Independent sitting Type III >18 months Independent stand and walk Type IV Second or third decade Normal Though classified into different types, SMA demonstrates a continuous range of severity and overlap 6 SMA, spinal muscular atrophy. 1. Kolb SJ & Kissel JT. Neurol Clin. 2015;33: ; 2. Wang CH, et al; Participants of the International Conference on SMA Standard of Care. J Child Neurol. 2007;22: ; 3. Prior TW & Russman BS. GeneReviews. Accessed Mar 2016; 4. Finkel RS, et al. Neurology. 2014;83: ; 5. Dubowitz V. Eur J Paediatr Neurol. 1999;3:49-51; 6. Arnold WD, et al. Muscle Nerve. 2015;51: Note: Copyright privileges for adapted table allow for inclusion in external presentations, but not for external distribution.

4 SMN GENES The SMN gene is present in multiple copies in the human genome: SMN1 (telomeric) SMN2 (centromeric) Most SMA patients have a SMN1 deletion, 2% denovo mutations SMN2 encodes a truncated mrna isoform A critical C > T nucleotide transition in SMN2 mrna results in a nonfunctional, rapidlydegraded protein (SMNΔ7) Severity of phenotype is correlated with SMN2 gene copies Telomeric SMN1 SMN1 pre-mrna SMN1 mrna 6 7 C Normal full-length SMN protein 8 Deletion of SMN1 ~90% Centromeric SMN2 mrna 6 SMN2 SMN2 pre-mrna 8 Nonoligomerizing unstable truncated SMN protein T Rapidly degraded C, centromeric; gdna, genomic deoxyribonucleic acid; mrna, messenger RNA; pre-mrna, precursor messenger RNA; SMA, spinal muscular atrophy; SMN, survival motor neuron; T, telomeric. 1. d Ydewalle C & Sumner CJ. Neurotherapeutics. 2015;12: ; 2. Prior TW & Russman BS. GeneReviews. Accessed Mar 2016; 3. Lunn MR & Wang CH. Lancet. 2008;371:

5 SMA INCIDENCE AND PREVALENCE SMA is a rare disorder SMA Type I has the highest incidence, yet the lowest prevalence, 1 due to its high mortality rate 2 The worldwide estimated annual incidence of SMA is cases per 100,000 live births 3-8 ~1:40 1:60 people are SMA carriers million and million individuals in the United States and Europe, respectively 8-10 In Israel, 2016, 1/52 11 SMA, spinal muscular atrophy. 1. Jones C, et al. Eur J Paediatr Neurol. 2015;19(suppl 1):S64-S65; 2. Lunn MR & Wang CH. Lancet. 2008;371: ; 3. Arkblad E, et al. Acta Paediatr. 2009;98: Tassie B, et al. J Paediatr Child Health. 2013;49: ; 5. Prior TW, et al. Am J Med Genet A. 2010;152A: ; 6. Jedrzejowska M, et al. Neuroepidemiology. 2010;34: ; 7. Ogino S, et al. Eur J Hum Genet. 2004;12: ; 8. Sugarman EA, et al. Eur J Hum Genet. 2012;20:27-32; 9. United States Census Bureau. U.S. and world population clock. Accessed Feb 2016; 10. World Population Statistics. Population of Europe Accessed Feb Personal communication Dr. Ami Zinger

6 DIAGNOSTIC DELAY IN SMA Data from a systematic literature review show that mean diagnostic delays were: (1.9) months for SMA Type I 14.3 (0) months for SMA Type II 43.6 (0) months for SMA Type III Data are mean (SD). SMA, spinal muscular atrophy. 1. Lin CW, et al. Pediatr Neurol. 2015;53: ; 2. Qian Y, et al. BMC Neurol. 2015;217

7 SMN2 BACK-UP GENE Normal SMN1 production SMN1 C SMN2 SMN2 production in patients with SMA SMN2 T SMN1 pre-mrna SMN2 pre-mrna SMN1 mrna SMN2Δ7 mrna 6 8 SMN2 mrna Normal full-length SMN protein Nonoligomerizing unstable truncated SMN protein Normal full-length SMN protein ~90% ~10% Rapidly degraded C, centromeric; mrna, messenger RNA; pre-mrna, precursor messenger RNA; SMA, spinal muscular atrophy; SMN, survival motor neuron; T, telomeric. 1. Lunn MR & Wang CH. Lancet. 2008;371: ; 2. Rossoll W & Bassell GJ. Results Probl Cell Differ. 2009;48:

8 Patients, % SMN2 COPY NUMBER MODIFIES SMA SEVERITY SMN2 copy number in patients with SMA Type I, II, and III SMN2 1 copy 2 copies 3 copies 4 copies A greater SMN2 copy number is correlated with a milder presentation of SMA 1 SMN2 copy number and SMA subtype are not perfectly correlated, so copy number is not diagnostic SMA (n=188) Type I (n=110) SMA Type II (n=77) SMA Type III SMA, spinal muscular atrophy; SMN, survival motor neuron. Data from: Feldkötter M, et al. Am J Hum Genet. 2002;70: Prior TW & Russman BS. GeneReviews. Accessed Mar 2016; 2. Wirth B, et al. Curr Opin Genet Dev. 2013;23:

9 MULTIDISCIPLINARY TEAM Pulmonologists/ respiratory therapists /intensivists Therapists OT/PT/ speech Social work Nurses and nurse practitioners Orthopedics Neurologists/ neuromuscular specialists Genetic counselors Primary care physicians Patient and family Nutritionists OT, occupational therapist; PT, physical therapist; SMA, spinal muscular atrophy. Wang CH, et al; Participants of the International Conference on SMA Standard of Care. J Child Neurol. 2007;22:

10 US PI 2016

11 WHAT ARE ANTISENSE OLIGONUCLEOTIDES (ASOS)? Short, synthetic nucleic acid chains 8 50 bp in length 1,2 Designed to bind to RNA based on complementary base pairing 1,2 broad range of potential effects Effects of ASOs are dependent on: 1 Class of RNA targeted Binding site Chemical composition of ASO ASO, antisense oligonucleotide; bp, base pair; RNA, ribonucleic acid. Figure modified from: Rigo F, et al. J Cell Biol. 2012;199: Rigo F, et al. J Cell Biol. 2012;199:21-25; 2. Evers MM, et al. Adv Drug Deliv Rev. 2015;87:90-103

12 ASOS CAN MODIFY SPLICING OF SMN2 Screening of ASOs showed that targeting ISS-N1 in intron 7 can increase inclusion of exon 7 These ASOs compete with hnrnp A1/2 for binding to the ISS-N1 site ASOs with certain chemical modifications promoted inclusion of exon 7 in the final transcript Without ASO Intron hnrnp A1/ Exons 6 8 With ASO ASO Intron ISS-N ASO, antisense oligonucleotide; hnrnp, heterogeneous nuclear ribonucleoprotein; ISS-N1, intronic splicing silencer N1; mrna, messenger RNA; SMN, survival motor neuron. Rigo F, et al. J Cell Biol. 2012;199:21-25 Note: Copyright privileges for adapted figure allow for inclusion in external presentations, but not for external distribution.

13 NUSINERSEN TREATMENT Pre treatment assessment: functional neurologic score(chop INTEND) Intrathecal First 3 doses in 2 weeks intervals. 4 th dose after one month & then every 3 months CHOP INTEND: Children s Philadelphia Hospital infant test of neurologic disorders

14 Other SMA populations Infantile-onset SMA CLINICAL STUDY PROGRAM: INFANTILE-ONSET AND OTHER SMA POPULATIONS CS3A: Open-label study in infantile-onset patients with SMA Phase 2; N=20 (est) NCT ENDEAR (CS3B): Randomized, double-blind, sham-procedure controlled Randomized 2:1; Phase 3; N=111 (est) NCT SHINE (CS11): OLE, Phase 3; N=274 (est) NCT NURTURE (CS5): Study in genetically diagnosed, presymptomatic infants Phase 2 open-label; N=25 (est) NCT Phase 2, sponsored by Ionis Pharmaceuticals Phase 3, sponsored by Ionis Pharmaceuticals Phase 2, sponsored by Biogen EMBRACE (CS7): Shamprocedure controlled study in patients not eligible for ENDEAR (CS3B) or CHERISH; N=21 (est) Phase 2; NCT EMBRACE: OLE Est, estimated; OLE, open-label extension; SMA, spinal muscular atrophy

15 CLINICAL STUDY PROGRAM: LATER-ONSET SMA CS1: Single ascending-dose Phase 1 open-label; N=28 NCT CS10: Redosing CS1 patients Phase 1 open-label; N=18 NCT CS2: Multiple ascending dose Phase 1/2a open-label; N=34 NCT CS12: Redosing CS2 and CS10 patients Phase 1 open-label; N=52 (est) NCT SHINE (CS11): OLE Phase 3; N=274 (est) NCT Phase 1 and 1/2a Phase 3 All studies sponsored by Ionis Pharmaceuticals CHERISH: Randomized, double-blind, sham-procedure controlled Randomized 2:1; Phase 3; N=117 (est) NCT SHINE (CS11): OLE Phase 3; N=274 (est) NCT Est, estimated; OLE, open-label extension; SMA, spinal muscular atrophy

16 NUSINERSEN IS DELIVERED INTRATHECALLY T11 T12 L1 L2 L3 L4 IT, intrathecal. Image modified from: Marieb EN & Hoehn K. Fundamentals of the nervous system and nervous tissue. In: Marieb EN & Hoehn K. Human Anatomy & Physiology. 10th ed. Upper Saddle River, NJ: Pearson; Evers MM, et al. Adv Drug Deliv Rev. 2015;87:90-103

17 % full-length SMN2 mrna CS3A: FULL-LENGTH SMN2 MRNA IN NUSINERSEN-TREATED INFANTS WITH SMA Healthy infants Nusinersentreated SMA Semiquantitative Untreated SMA RT-PCR analysis A B C W X Y Z Full-length SMN2 mrna SMN2 mrna 6 8 Truncated SMNΔ7 mrna Lancet.Dec.2016 % full-length SMN A 19 B 26 C 20 W X Y mrna, messenger RNA; RT-PCR, reverse transcriptase polymerase chain reaction; SMA, spinal muscular atrophy; SMN, survival motor neuron. Data are from autopsy samples (control, n=3 [patients A, B, and C]; untreated SMA, n=4 [patients W, X, Y, and Z]; nusinersen-treated SMA, n=3 [patients 1, 2, and 3]). Numbers and letters denote individual patients. Finkel RS, et al. Lancet. Epub Dec 6, doi: /s (16) Z % full-length SMN2 by group Healthy infants / untreated SMA = Nusinersen-treated SMA = Corresponds to a 2.6-fold increase Note: Copyright privileges for adapted figure allow for inclusion in external presentations, but not for external distribution.

18 Mean (SE) HINE total motor milestone score NURTURE (CS5) INTERIM ANALYSIS MEAN HINE TOTAL MOTOR MILESTONE SCORE OVER TIME In general, all enrolled infants demonstrated increased motor milestone scores from Baseline to last evaluation Maximum total score, 26 points 2 SMN2 copies, n 3 SMN2 copies, n Total, n Study visit day SMN2 copies 3 SMN2 copies Total 1 1 HINE, Hammersmith Infant Neurological Exam; SE, standard error; SMN, survival motor neuron. NURTURE (Cs5) study interim analysis data cutoff date: Jun 8, Bertini E, et al. WMS 2016

19 Mean (SE) CHOP INTEND total score NURTURE (CS5) INTERIM ANALYSIS (JUNE 2016): MEAN CHOP INTEND TOTAL SCORE OVER TIME 10/13 (77%) infants achieved increases (range, 4 20 points) 3/13 (23%) experienced decreases (range, 2 3 points) Maximum total score, 64 points Baseline median (range) CHOP INTEND total score was 55.0 (39 60) points in the total efficacy population CHOP INTEND total scores in infants with SMA 6 months of age from a natural history study ranged from points 1 2 SMN2 copies, n 3 SMN2 copies, n Total, n SMN2 copies 3 SMN2 copies Total Study visit day CHOP INTEND, Children s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; SMA, spinal muscular atrophy; SE, standard error; SMN, survival motor neuron. NURTURE (CS5) study interim analysis data cutoff date: Jun 8, Kolb SJ, et al; NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators. Ann Clin Transl Neurol. 2016;3: Bertini E, et al. WMS 2016

20 Mean (SE) change from Baseline CS2 AND CS12: CHANGE IN HFMSE SCORE OVER TIME IN SMA TYPE II (CS12 INTERIM ANALYSIS, APRIL ) Maximum possible HFMSE score: 66 1 Mean (SE) Baseline HFMSE score: 21.3 (2.9) Mean (SE) change with nusinersen of: 5.1 (1.2) points at Day (2.2) points at Day Improvement In a natural history cohort of SMA Type II and III, mean change was 0.5 points over 24 months (730 days) and 1.7 points over 36 months (1095 days) 2 No. of patients Study visit (Day) HFMSE, Hammersmith Functional Motor Scale Expanded; SE, standard error; SMA, spinal muscular atrophy. Data cutoff date: Aprl 7, 2016 (CS12 interim analysis). 1. O Hagen JM, et al. Neuromuscul Disord. 2007;17: ; 2. Kaufman P, et al; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR). Neurology. 2012;79: Darras BT, et al. WMS 2016

21 Mean (SE) change from Baseline CS2 AND CS12: CHANGE IN ULM TEST TOTAL SCORE OVER TIME IN SMA TYPE II (CS12 INTERIM ANALYSIS, 7 APRIL 2016) 6 Maximum possible ULM test total score is 18 in nonambulatory patients with SMA 1 Mean (SE) Baseline ULM test total score: 11.9 (0.9) Mean (SE) change with nusinersen of: 1.9 (0.8) points at Day (1.4) points at Day 1050 In a natural history cohort of nonambulatory patients with SMA, mean change was 0.04 points over 12 months 2 Study visit (Day) No. of patients Improvement SE, standard error; SMA, spinal muscular atrophy; ULM, upper limb module. Data cutoff date: Apr 7, 2016 (CS12 interim analysis). 1. Mazzone E, et al. Neuromuscul Disord. 2011;21: ; 2. Sivo S, et al. Neuromuscul Disord. 2015;25: Darras BT, et al. WMS 2016

22 Mean (SE) change from Baseline CS2 AND CS12: CHANGE IN HFMSE SCORE OVER TIME IN SMA TYPE III (CS12 INTERIM ANALYSIS, APRIL ) 5 Maximum possible HFMSE score: 66 1 Mean (SE) Baseline HFMSE score: 48.9 (3.0) Mean (SE) change with nusinersen of: 1.3 (0.5) points at Day (1.5) points at Day Improvement In a natural history cohort of SMA Type II and III, mean change was 0.5 points over 24 months (730 days) and 1.7 points over 36 months (1095 days) 2-1 No. of patients Study visit (Day) HFMSE, Hammersmith Functional Motor Scale Expanded; SE, standard error; SMA, spinal muscular atrophy. Data cutoff date: Apr 7, 2016 (CS12 interim analysis). 1. O Hagen JM, et al. Neuromuscul Disord. 2007;17: ; 2. Kaufman P, et al; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR). Neurology. 2012;79: Darras BT, et al. WMS 2016

23 Mean (SE) change from Baseline, m CS2 AND CS12: CHANGE IN 6MWT IN SMA TYPE III (CS12 INTERIM ANALYSIS, APRIL 2016) 125 Baseline 6MWT distance: (50.7) meters 100 Mean (SE) change with nusinersen of: 28.6 (13.6) meters at Day (17.3) meters at Day 1050 Natural history is mean 1.5-meter change over 12 months 1 One patient with SMA Type II gained the ability to walk independently Two patients with SMA Type III regained the ability to walk independently No. of patients Study visit (Day) Improvement 6MWT, 6-Minute Walk Test; SE, standard error; SMA, spinal muscular atrophy. Data cutoff date: Apr 7, 2016 (CS12 interim analysis). 1. Mazzone E, et al. Neuromuscul Disord. 2013;23: Darras BT, et al. WMS 2016

24 CS3A INTERIM ANALYSIS (JANUARY 2016): MOST COMMON AES ( 20% PATIENTS) BY MEDDRA PT 100% of patients reported 570 AEs Two possible drug-related AEs were reported: Mild decreased transient, asymptomatic neutropenia Mild event of vomiting MedDRA PT 6 12 mg nusinersen n=4 No. of events (% of patients) 12 mg nusinersen n=16 No. of events (% of patients) Total N=20 No. of events (% of patients) Any AE 110 (100) 460 (100) 570 (100) Pyrexia 5 (75) 32 (69) 37 (70) Respiratory infection 10 (75) 28 (69) 38 (70) Constipation 1 (25) 9 (50.0) 10 (45) Vomiting 2 (50) 11 (38) 13 (40) Joint contracture 15 (75) 9 (31) 24 (40) Pneumonia 2 (25) 15 (38) 17 (35) Scoliosis 2 (50) 6 (31) 8 (35) Respiratory distress 2 (25) 10 (38) 12 (35) Nasal congestion 3 (25) 8 (38) 11 (35) Respiratory failure 0 7 (38) 7 (30) Rhinovirus infection 0 7 (38) 7 (30) AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; PT, Preferred Term. Data cutoff date: Jan 26, Finkel RS, et al. Lancet. Epub Dec 6, doi: /s (16)

25 CS3A INTERIM ANALYSIS (JANUARY 2016): MOST COMMON AES ( 20% PATIENTS) A BY MEDDRA PT (CONT.) MedDRA PT 6 12 mg nusinersen n=4 No. of events (% of patients) 12 mg nusinersen n=16 No. of events (% of patients) Total N=20 No. of events (% of patients) Any AE 110 (100) 460 (100) 570 (100) Nasopharyngitis 0 13 (38) 13 (30) Gastroesophageal reflux 0 6 (38) 6 (30) Otitis media 1 (25) 7 (31) 8 (30) Cough 2 (50) 8 (25) 10 (30) Diarrhoea 1 (25) 13 (25) 14 (25) Actelactasis 0 9 (31) 9 (25) Increased secretions 0 7 (31) 7 (25) Rash 4 (25) 6 (25) 10 (25) AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; PT, Preferred Term. Data cutoff date: Jan 26, Finkel RS, et al. Lancet. Epub Dec 6, doi: /s (16)

26 CHERISH STUDY NEWSLETTER RESULTS Phase III study Late onset SMA: age 2-12 years Sham procedure control 2:1,N= months follow-up a significant difference (p = ) of 5.9 points in HFMSE, between patients given NUSINERSEN (n = 84) compared to the sham control procedure (n = 42). All patients continued to open label SHINE study

27 SUMMARY SMA is a life limiting disease Nusinersen is an ASO aimed to treat the underlying cause of SMA It is a life saving life prolonging agent, treating all SMA types Clinical trials were stopped and nusinersen was FDA approved on December 2016

28 NUSINERSEN TREATMENT EXPERIENCE IN ISRAEL? Compassionate treatment for 6 patients from Biogen Started treatment at Dana hospital: 5 One received 4 doses & one 3 doses

29 AVXS-101 Clinical update As presented at the World Muscle Society, October 2016

30 AVXS-101 (AAV9 CAPSID SHELL) A non-replicating adeno-associated virus (AAV9) capsid, deliver a functional copy of a human SMN Crosses the blood-brain barrier Preclinical studies: AAV9 (IV & IT) efficiently target motor neuron cells AVXS-101 aims to introduce a fully functional SMN gene to increase the patient's production of SMN protein to an adequate level.

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42 THANKS Dr. Sharon Aharoni. SCMCI Dr. Liora Sagi. Dana hospital Dr. Yael Gruenbaum-Cohen. Medison-Biogen

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44 SMN-DEPENDENT RNP ASSEMBLY PATHWAYS AND THEIR LINK TO SMA Gemin4 Gemin3 Gemin5 Gemin8 Gemin6 Gemin7 SMN is essential for the assembly of the heteroheptameric ring of Sm proteins on snrnas, which is an obligate step in the biogenesis pathway of key RNP components of the RNA splicing machinery 1,2 Evidence points to a role for spliceosomal snrnp dysfunction in SMA 2 Defects in snrnp assembly correlate with disease severity and lead to a reduction in the steady-state levels of snrnps in mouse models of SMA snrnps of the minor spliceosome that carry out U12-dependent splicing are more strongly affected than those of the major spliceosome SMN deficiency induces prominent snrnp reduction in motor neurons compared with other neurons and non-neuronal cells in the spinal cord of SMA mice Proteins RNAs Function G D3 E B D1 D2 F D3 G E SMN SMN SMN Gemin2 Gemin2 Gemin2 B F Unrip Sm Sm/LSm LSm2-8 LSm1-7 RBPs U1, U2, U4, U5 U11,U12,U4atac pre-mrna splicing U7 Histone mrna 3 processing U6 U6atac Pre-mRNA splicing SMA mrnas mrna decay HuD hnrnp R KSRP IMP1 mrnas mrna transport/stability Solid arrows indicate connections that are established both molecularly and functionally. hnrnp, heterogeneous nuclear ribonucleoprotein; IMP1, IGF2 mrna-binding protein 1; KSRP, KH-type splicing regulatory protein; LSm, Sm-like; mrna, messenger RNA; pre-mrna, precursor messenger RNA; RBP, RNA-binding protein; RNP, ribonucleoprotein; SMA, spinal muscular atrophy; SMN, survival motor neuron; snrna, small nuclear RNA. 1. Li DK, et al. Sem Cell Dev Biol. 2014;32:22 29; 2. Tisdale S & Pellizzoni L. J Neurosci. 2015;35: Note: Copyright privileges for adapted figure allow for inclusion in external presentations, but not for external distribution.