management of SMA: Multidisciplinary perspectives SMA, spinal - - PowerPoint PPT Presentation

Presentation, diagnosis and management of SMA: Multidisciplinary perspectives

SMA, spinal muscular atrophy.

Dr Eduardo Tizzano

Director of the Department of Clinical and Molecular Genetics, Hospital Vall d’Hebron, Barcelona, Spain

What are the emerging treatments for SMA patients and how can these address unmet needs in clinical practice?

SMA, spinal muscular atrophy.

Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. The presenting faculty have been advised by touchIME to ensure that they disclose any such references made to unlabelled or unapproved use. No endorsement by touchIME of any unapproved products or unapproved uses is either made or implied by mention of these products or uses in touchIME activities. touchIME accepts no responsibility for errors or omissions.

Disclaimer

Mode of action of available SMN-enhancing therapies

*Regulatory approval of AVXS-101 and nusinersen may vary with geographic location. SMA, spinal muscular atrophy; SMN, survival motor neuron.

• 1. Bowerman M, et al. Dis Model Mech. 2017;10:943–954. 2. Calucho M, et al. Neuromuscul Disord. 2018;28(3):208–215.

➢ Clinical severity of SMA is related to number of SMN2 copies, with a lower copy number being linked to more severe types of SMA.1,2

Healthy individual1 SMA patient2

SMN1 gene SMN2 gene 100% full-length SMN protein ~10% full-length SMN protein ~90% SMN protein lacking exon 7 (non-functional) SMN1 gene SMN2 gene 0% full-length SMN protein ~10% full-length SMN protein ~90% SMN protein lacking exon 7 (non-functional)  SMN2 copy number =  full-length SMN  SMN2 copy number =  full-length SMN AVXS-101* (onasemnogene abeparvovec)

• Delivers a functional copy of SMN1,

increasing full-length SMN production Nusinersen*

• Antisense oligonucleotide promotes

transcription of full-length SMN2

Efficacy and safety of nusinersen

AE, adverse event; HFMSE, Hammersmith Functional Motor Scale–Expanded; HINE-2, Hammersmith Infant Neurologic Examination Part 2; mo, months; SMA, spinal muscular atrophy; SMN, survival motor neuron; SAE, serious adverse event.

• 1. Finkel RS, et al. New Engl J Med. 2017;377:1723–32. 2. Mercuri E, et al. New Engl J Med. 2018;378:625–635. 3. De Vivo D, et al. Neuromuscul Disord 2019;29:842–856.

CHERISH2: 126 patients with SMA2 (symptom onset >6 mo)

• Interim analysis

Mean increase in HFMSE score:

• +4 points vs -1.9 points (control)
• Least mean squares difference

5.9 points; p<0.001

• Similar AE incidence between groups

ENDEAR1: 121 patients with SMA1 (<7 mo old with symptom onset at <6 mo)

• Final analysis (n=110)
• Achievement of HINE-2 milestones:
• Similar AE incidence between groups, and

fewer SAEs with nusinersen Control group: 0% all milestones 22% full head control 10% able to roll over 8% independent sitting 1% able to stand NURTURE3: 25 patients with SMA and two or three SMN2 copies (presymptomatic)

• At interim analysis with 2.9 years of follow-up:
• All patients were alive and none required tracheostomy
• r permanent ventilation
• 100% could sit without support
• 92% could walk with assistance
• 88% could walk independently

Efficacy and safety of AVXS-101

CHOP-INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale; mo, months; SMA, spinal muscular atrophy.

• 1. Mendell JR, et al. New Engl J Med. 2017;377:1713–1722. 2. Novartis. https://www.novartis.com/news/media-releases/avexis-data-reinforce-effectiveness-zolgensma-

treating-spinal-muscular-atrophy-sma-type-1 (accessed December 2019).

START study1

• Two Grade 4 elevated

aminotransferases considered treatment related

patients required permanent ventilation

+7.7

mean increase in CHOP-INTEND with low dose (n=3)

+24.6

mean increase in CHOP-INTEND with high dose (n=12)

CHOP-INTEND score:

15 patients SMA1, age <8 mo Symptoms at ≤3 mo

When all patients had reached ≥20 mo:

STR1VE study2 22 patients with SMA1 <6 mo at treatment Mean +7 points after 1 month Mean +11.8 points after 3 months

Small molecule SMN-enhancing drugs in development

SMN; survival motor neuron.

• 1. Bowerman M, et al. Dis Model Mech. 2017;10:943–954. 2. Poirier A, et al. Pharmacol Res Perspect. 2018;6(6):e00447. 3. Calder AN, et al. J Med Chem. 2016;59(22):10067–10083.

SMN2 splicing modifiers: risdiplam and branaplam

SMN2:

~90% of SMN protein from SMN2 is transcribed without exon 7 and is non-functional1 6 7 8 6 8

SMN2:

6 7 8 6 8 Splicing modifiers promote the transcription of full- length, functional SMN protein including exon 72,3 7 non-functional functional

• These agents are orally administered and distribute to peripheral tissues as well as the central nervous system2,3

Non-SMN-directed options in development

SMN, survival motor neuron.

• 1. Shorrock HK, et al. Drugs. 2018;78:293–305. 2. Pera MC, et al. Neuromuscul Disord. 2018;28(10):863–864. 3. Stam M, et al. BMJ Open. 2018;8(7):e019932. 4. Bowerman M, et al. Dis

Model Mech. 2017;10:943–954. 5. SMA News Today. https://smanewstoday.com/ck-2127107-ck-107-cytokinetics-astellas (accessed December 2019). 6. Cote SM, et al. SLAS Discov. 2019 Jul 26. doi: 10.1177/2472555219860779 (Epub ahead of print).

Neuroprotective agents1 Neuromuscular junction stabilizers

• Salbutamol is a β2-adrenoreceptor

agonist which may act at the neuromuscular junction2

• Pyridostigmin is an acetylcholinesterase

inhibitor that improves neuromuscular transmission3

Skeletal muscle activation

• Reldesemtiv is a fast skeletal troponin activator

which increases muscle contractility4,5

• SRK-015 enhances muscle mass via myostatin

inhibition6

These approaches could potentially be combined with SMN-enhancing therapies4

MDT considerations for SMN-enhancing therapies1-3

MDT, multidisciplinary team; SMN, survival motor neuron.

• 1. NeurologyToday. https://journals.lww.com/neurotodayonline/Fulltext/2019/04180/Two_New_Treatments_for_Spinal_Muscular_Atrophy_May.8.aspx (accessed December 2019).
• 2. Farrar MA, et al. Ann Neurol. 2017;81:355–368. 3. Tizzano EF, Finkel RS. Neuromuscul Disord. 2017;27:883–889.

Cost:benefit ratio Relative inexperience and evolving phenotypes with new treatments Need for earlier (pre-symptomatic) diagnosis