gene therapy in mnd
TRANSCRIPT
Gene Therapy in MNDUniversity of Sheffield
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document without a watermark .
ROS
MND
• A genetic therapy for familial MND caused by SOD1 mutation
• 1% of all MND
MND uncertainty
Faulty DNA Faulty mRNA
Buy SmartDraw!- purchased copies print this
document without a watermark .
B u
y S
m a
rt D
ra w
document without a watermark .
ROS
document without a watermark .
B u
y S
m a
rt D
ra w
X X
Enzymatic degradation
• > 18 years old
Primary
• 7 from Sheffield
• Five doses of study treatment (tofersen or placebo)
• Approximately 31 weeks including: up to 7-week screening period, 12-week dosing
period, and 12-week follow-up period
Objective: to evaluate the safety, tolerability, PK, PD, and exploratory efficacy of an antisense oligonucleotide
tofersen (BIIB067/IONIS-SOD1Rx) designed to degrade superoxide dismutase 1 (SOD1) mRNA to reduce levels of
SOD1 protein in people with ALS with SOD1 gene mutation (SOD1-ALS)
Lowering of SOD1 and biomarker neurofilament levels
• 37% lowering of SOD1 in CSF at highest dose 100 mg vs. no reduction in placebo group, p=0.002)
** First identification of biomarkers of therapeutic efficacy
0 . 6
0 . 8
1 . 0
1 . 2
G e
o m
e t
2 0 m g ( n = 9 )
4 0 m g ( n = 9 )
6 0 m g ( n = 9 )
1 0 0 m g ( n = 1 0 )
1 5 2 9 5 7 8 5
SOD1 CSF Concentration
CSF NfL levels
Other Positive Findings
-8
-4
0
O v e ra ll p la ce b o (n = 1 2 )
O ve ra ll to fe rs e n 1 0 0 m g (n = 1 0 )
F P p la c e b o (n = 4 a )
F P to fe rs e n 1 0 0 m g (n = 4 )
M e
a n
-5
0
5
O v e ra ll p la ce b o (n = 1 2 )
O ve ra ll to fe rs e n 1 0 0 m g (n = 1 0 )
F P p la c e b o (n = 4 )
F P to fe rs e n 1 0 0 m g (n = 4 )
15 29 57 85
-1 .0
-0 .5
0 .0
0 .5
1 .0
O v e ra ll p la c e b o (n = 1 1 )
O v e ra ll to fe rs e n 1 0 0 m g (n = 1 0 )
F P p la c e b o (n = 4 )
F P to fe rs e n 1 0 0 m g (n = 4 )
22 92
maintained Limbs remain strong
Phase 2/3 study enrolled
Reporting 2021
What does this mean for the other 99%? MND could be treatable
• For 10% with familial MND multiple promising gene trials
• C9orf72 underway
• For 90% with sporadic MND
• Understanding of sporadic MND has made major advances in recent years with many potential new treatments ready to be tested
• Faster and smarter clinical trials using biomarker readouts and platform trial designs
• Learning from familial MND
• Advances in understanding of biology
• Trial design and execution
document without a watermark .
B u
y S
m a
rt D
ra w
document without a watermark .
ROS
MND
• A genetic therapy for familial MND caused by SOD1 mutation
• 1% of all MND
MND uncertainty
Faulty DNA Faulty mRNA
Buy SmartDraw!- purchased copies print this
document without a watermark .
B u
y S
m a
rt D
ra w
document without a watermark .
ROS
document without a watermark .
B u
y S
m a
rt D
ra w
X X
Enzymatic degradation
• > 18 years old
Primary
• 7 from Sheffield
• Five doses of study treatment (tofersen or placebo)
• Approximately 31 weeks including: up to 7-week screening period, 12-week dosing
period, and 12-week follow-up period
Objective: to evaluate the safety, tolerability, PK, PD, and exploratory efficacy of an antisense oligonucleotide
tofersen (BIIB067/IONIS-SOD1Rx) designed to degrade superoxide dismutase 1 (SOD1) mRNA to reduce levels of
SOD1 protein in people with ALS with SOD1 gene mutation (SOD1-ALS)
Lowering of SOD1 and biomarker neurofilament levels
• 37% lowering of SOD1 in CSF at highest dose 100 mg vs. no reduction in placebo group, p=0.002)
** First identification of biomarkers of therapeutic efficacy
0 . 6
0 . 8
1 . 0
1 . 2
G e
o m
e t
2 0 m g ( n = 9 )
4 0 m g ( n = 9 )
6 0 m g ( n = 9 )
1 0 0 m g ( n = 1 0 )
1 5 2 9 5 7 8 5
SOD1 CSF Concentration
CSF NfL levels
Other Positive Findings
-8
-4
0
O v e ra ll p la ce b o (n = 1 2 )
O ve ra ll to fe rs e n 1 0 0 m g (n = 1 0 )
F P p la c e b o (n = 4 a )
F P to fe rs e n 1 0 0 m g (n = 4 )
M e
a n
-5
0
5
O v e ra ll p la ce b o (n = 1 2 )
O ve ra ll to fe rs e n 1 0 0 m g (n = 1 0 )
F P p la c e b o (n = 4 )
F P to fe rs e n 1 0 0 m g (n = 4 )
15 29 57 85
-1 .0
-0 .5
0 .0
0 .5
1 .0
O v e ra ll p la c e b o (n = 1 1 )
O v e ra ll to fe rs e n 1 0 0 m g (n = 1 0 )
F P p la c e b o (n = 4 )
F P to fe rs e n 1 0 0 m g (n = 4 )
22 92
maintained Limbs remain strong
Phase 2/3 study enrolled
Reporting 2021
What does this mean for the other 99%? MND could be treatable
• For 10% with familial MND multiple promising gene trials
• C9orf72 underway
• For 90% with sporadic MND
• Understanding of sporadic MND has made major advances in recent years with many potential new treatments ready to be tested
• Faster and smarter clinical trials using biomarker readouts and platform trial designs
• Learning from familial MND
• Advances in understanding of biology
• Trial design and execution