Emerging Therapies for SMA. Francesco Muntoni

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1 Emerging Therapies for SMA Francesco Muntoni TREAT-NMD Alliance Conference 2013 Newcastle Dubowitz Neuromuscular Centre UCL Institute of Child Health & Great Ormond Street Hospital London

2 Therapeutic targets for SMA example Mutation of smn1 Replacement of SMN1 Gene therapy Alternative splicing of smn2 Inclusion of exon 7 Antisense Pharmacological upregulation Diminution of fulllength smn transcript Increase of SMN transcripts HDAC inhibitors Hydroxyurea Quinazolones SMN protein deficit Stabilisation of SMN protein Indoprofen Proteasome inhibitors Polyphenols Loss of motorneurons Clinical symptoms Neuroprotection Cell therapy Riluzole, TRO19622 Neurotrophic factors Stem cells

3 SMN splicing DNA p44 NAIPΨ SMN2 SMN1 NAIP p44 Type I mrna % Fl.SMN % % Δ7.SMN Full length SMN protein SMA patients are depleted of full length SMN protein. The small amount of SMN protein in these patients derives from the inefficient inclusion of SMN exon 7 in SMN2 transcript (~10% of all transcript) Type III

4 Modifying SMN2 splicing With antisense oligonucleotides With pharmacological agents

5 ISIS-SMN Rx : Modulating Splicing of SMN2 to Increase Normal SMN Protein 5 Uniformly 2 -O-methoxyethyl modified (MOE) antisense drug Corrects the splicing disorder in SMN2, resulting in the production of fully functional SMN protein in model systems In mild and severe mouse models of SMA provides a phenotypic and pathological benefit when delivered centrally* Distributes broadly to spinal cord motor neurons after intrathecal delivery in monkeys* Has a long half life in CNS tissue (>6 months in animal models) HO O O S P O O O O B O O OCH 3 B OCH 3 SMN2 Gene SMN2 Gene C to T C to T 1 2 a 2b a 2b SMN2 mrna ISIS-SMN Rx SMN2 mrna Defective Protein, missing exon 7 Functional Protein *(Hua et al., Genes Dev., 2010; Passini et al., Sci Transl Med, 2011; Hua et al., Nature, 2011)

6 SMN Targeting ASO Preserves Neuron and Muscle Function in a Mouse Model of SMA SMN Targeting ASO Preserves Neuromuscular Junctions ISIS SMN Rx SMN Targeting ASO Maintains Muscle Fiber Size ISIS SMNRx ISIS SMN Rx 6

7 Clinical Program for ISIS-SMN Rx Orphan Drug Status in US and EU; Fast Track Designation in USA Phase 1 Single-dose Study in Children with SMA completed - ISIS-SMN Rx well tolerated, no safety concerns identified - Preliminary, but encouraging changes in HFMSE scores observed at highest dose Phase 1b/2a Multiple-dose Study in Children with SMA - ongoing Phase 2 Multiple-dose Study in Infants with SMA - ongoing Two pivotal, controlled studies planned to start in 2014, to be conducted worldwide, including Europe -Phase 2/3 study in Infants with SMA -Phase 2/3 study in Children with SMA

8 Phase 1 open label, single dose study in SMA II-III patients 2-14 years of age.

9 9 Long-term Follow-Up HFMSE Scores of Type 2/3 SMA Subjects in Single-dose Study (full study data at Mean + SEM At 9 to 14 months post-dose, mean change from baseline in HFSME = -1.7, 0.5, 2.5, and 5.75 for 1, 3, 6, and 9 mg groups respectively 9 mg group mean change from baseline = 5.75 points (p = 0.008), % change = 32.8%; no 9 mg subjects had declined (range = 1 to 14 point improvement)

10 Other antisense backbones Morpholino backbone chemistry is at least as effective than MOE, but direct ICV administration still required

11 Strategies to target AOs to the Central Nervous System a.incapsulate the AO with small particles b.link the AON directly to a targeting peptide c. use other modifications of backbone

12 B peptide MSP -GGCCAAACCTCGGCTTACCTGAAAT

13 Tricyclo-DNA Platform As LNA, tc-dna has been designed as a CONFORMATIONALLY CONSTRAINED oligonucleotide analogue. Chemical modifications change the properties of natural oligodeoxynucleotides by: Increased RNA AFFINITY by 2-4 C / modification; Increased HYDROPHOBICITY; Increased STABILITY towards nucleolytic degradation for both, phosphate or thiophosphate internucleoside linkages; Inability to elicit RNaseH activity. Unlike LNA, tc-oligonucleotides in the LENGTH RANGE OF nucleotides can easily be prepared and produce potent antisense effects. Courtesy of V. Robin

14 Pharmacological modification of SMN2 splicing In vitro activity of SMN2 splicing modifiers SMN protein increase in Type I SMA fibroblasts

15 Discovery/Optimization of Quinazolines for Potential Treatment of SMA SMN2 promoter assay-based HTS run by Aurora (subsequently Vertex) Jarecki et al. (2005) Hum. Mol. Genet. 14(14): N NH 2 Hit/Lead optimization by DeCODE Chemistry Inc. using promoter assay O N NH 2 Thurmond et al. (2008) J. Med. Chem. 51: N DcpS (scavenger decapping enzyme) identified as putative target of C5-substituted quinazolines by decode Chemistry Inc. Singh et al. (2008) ACS Chem. Biol. 3(11): F D Demonstration of increased Smn promoter activity in vivo in CNS of SMA mice by 2,4-diaminoquinazoline derivatives and increased in survival by D Butchbach et al. (2010) Hum. Mol. Genet. 19(3):

16 Discovery/Optimization of Quinazolines for Potential Treatment of SMA, continued 2009: Program licensed from Families of SMA to RepliGen RepliGen selects D (RG3039) as clinical lead 2011: RG3039 enters the clinic supported by a grant from Muscular Dystrophy Association Beneficial effects of RG3039 demonstrated in 3 different SMA mouse models Gogliotti et al. (2013) HMG. 22(20): Van Meerbeke et al. (2013) HMG. 22 (20) : Jan 2013: Announcement of program being licensed from RepliGen to Pfizer 16

17 Gene Therapy

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20 A clinical trial of olesoxime (TRO19622) in SMA Trophos Study sites: 22 sites in France, Germany, Italy, UK, Poland, Netherlands, Belgium Total number of subjects: 150 patients in total, 100 in the olesoxime group, and 50 in the placebo group. Study duration: Total of 33 months with a 9 months recruitment period and a 2 years treatment period Outcome of the study expected 4Q2013

21 Acknowledgements Neuromuscular Translational Research Centre London and Newcastle