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subgroups and populations Dr David Kallend MBBS Chief Medical - - PowerPoint PPT Presentation
subgroups and populations Dr David Kallend MBBS Chief Medical - - PowerPoint PPT Presentation
Efficacy and safety of inclisiran, an RNAi therapeutic targeting PCSK9: Analysis of dosage in different Phase II subgroups and populations Dr David Kallend MBBS Chief Medical Officer The Medicines Company 1 Disclosures Dr David Kallend is a
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New data announced today: Consistent efficacy and duration of effect across different trials & populations In addition: Pivotal trials of 18 m duration fully enrolled (N=3,660) after rapid recruitment Accumulating high-quality safety data for inclisiran at 5 patient years per day Further studies to commence in 2018
Inclisiran clinical trials program
Inclisiran development ahead of schedule
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4 Reproduced with permission from Alnylam Pharmaceuticals
RNAi therapeutics
A new class of innovative medicines
Harness natural catalytic mechanism Silence any gene in genome Nobel Prize-winning science Potent and durable mechanism of action Product engine for sustainable pipeline
U G U C U A A A U C G U A G A G U A A T T
P
Antisense strand
A C A G A U U U A G C A U C U C A U U
mRNA
= ≡ = = = = = = = = = = = ≡ ≡ ≡ ≡ ≡
RISC
RNA-induced Silencing Complex (RISC)
- 1. RISC
Loading
- 2. Sense
Strand Removal
- 3. Target
Recognition
- 4. Target
Cleavage
U G U C U A A A U C G U A G A G U A A T T
P
= ≡ = = = = = = = = = = = ≡ ≡ ≡ ≡ ≡
A C A G A U U U A G C A U C U C A U U
Watson-Crick base pairs
- 5. Catalytic
Mechanism
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5 1. Ray KK et al. NEJM 2017; 376: 1430-40
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10 30 60 90 120 150 180 210 240 270 300 330 360
6-months time-averaged LDL-C reduction = 51%
Starting Maintenance Next dose day 450 Mean percent change (±95% CI) Days from first injection
ORION-1: Dose finding study in ASCVD and ASCVD risk equivalents
Effect of two starting doses of inclisiran 300 mg vs. placebo s.c.
Placebo s.c. Inclisiran 300 mg s.c.
Ray et al. N Engl J Med 2017; 376:1430-1440
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ORION-1: Dose finding study in ASCVD and ASCVD risk equivalents
LDL-C and PCSK9 reduction at day 180 after two starting doses
Group Subgroup N Mean LDL-C reduction Mean PCSK9 reduction All subjects 59
- 52.5%
- 69.1%
Diabetes Yes 7
- 55.3%
- 70.8%
No 52
- 52.2%
- 68.8%
Renal function Normal 14
- 55.2%
- 72.6%
Mild 39
- 50.6%
- 67.3%
Moderate 6
- 56.8%
- 72.3%
Statin Yes 49
- 53.3%
- 68.6%
No 10
- 48.5%
- 71.2%
MDCO Data on File
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AE profile generally similar to placebo and across major subgroups
- No LFT elevations related to drug
- No difference in incidence of myalgia or CPK enzyme elevation
- No thrombocytopenia
- No neuropathy
- No immunogenicity (absence of anti-drug antibodies in ~6,000 samples)
- No pro-inflammatory symptoms or elevated markers
Two deaths related to underlying ASCVD ORION-1: Dose finding study in ASCVD and ASCVD risk equivalents
No safety concerns in any patient group at any dose
Ray et al. N Engl J Med 2017; 376:1430-1440
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Subject #2 Asp227Glu/Asp227Glu variant Previous non-responder to mAbs No observed LDL-C reduction despite consistent and durable PCSK9 reduction
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20 40 50 100 150 200 Days
Subject 2
LDL-C PCSK9 Lp(a)
ORION-2: HoFH Pilot study
Standard dose 300mg Day 1 and 90
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Subject #3 Asp227Glu/Val429Met variant LDL-C reduction:
- 16.7% at day 60
- 32.8% at day 120
- 30.5% at day 180
- 19.6% at Day 300
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- 50
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10 20 30 50 100 150 200 250 300 350 Days
Subject 3
LDL-C PCSK9 Lp(a)
ORION-2: HoFH Pilot study
Standard dose 300mg Day 1 and 90
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Subject #4 Asp227Glu/Asp227Glu variant LDL-C reduction
- 29.5% at day 60
- 44.3% at day 120
- 38.8% at day 180
- 24.9% at Day 300
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10 20 50 100 150 200 250 300 350 Days
Subject 4
LDL-C PCSK9 Lp(a)
ORION-2: HoFH Pilot study
Standard dose 300mg Day 1 and 90
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Plasma PK over the first 48 hours Exposure with renal dysfunction – as anticipated inclisiran not detectable in any group after 48 hours
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10 20 30 40 50 60 Percent change in PCSK9 Days
PD effects on PCSK9 not significantly different
Normal Mild Moderate Severe
ORION-7: Renal impairment study
No dose adjustments needed for impaired renal function
Group Cmax ng/mL AUC h*ng/mL Normal 421 7,600 Mild 987 11,800 Moderate 897 13,433 Severe 1,756 19,214
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- Additional clinical pharmacology studies for hepatic, renal impairment and for TQT
- Pediatric studies
ORION Phase III trials
Pivotal Phase III studies to support LDL-C lowering labeling
Study Sites Main inclusion criteria Patients ORION-11 EU, SA ASCVD (LDL-C >70mg/dL) and risk equivalent patients (LDL-C >100 mg/dL) 1,617 ORION-10 US ASCVD (LDL-C >70 mg/dL) 1,561 ORION-9 US, EU, SA Heterozygous FH 482 ORION-5 US, EU, SA Homozygous FH 40 3700
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Aims To assess the effect of inclisiran on major cardiovascular events The study will randomize ≥15,000 participants aged ≥55 years with pre- existing cardiovascular disease between inclisiran sodium 300 mg and matching placebo for a median of about 5 years. HPS-4/TIMI 65/ORION-4: CVOT study
Planned study design
Primary endpoint Composite of major adverse cardiovascular events (MACE), defined as:
- Coronary (CHD) death; or
- Myocardial infarction; or
- Fatal or non-fatal ischaemic stroke; or
- Urgent coronary revascularization
procedure
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Rapid accumulation of safety data
- 5 patient-years on inclisiran per day
10-fold increase during 2018
- 1,800 with 3 doses
- 300 with 4 – 5 doses
26 230 2360
Phase I Phase II End of 2018
Patient-years exposure to inclisiran Inclisiran clinical trials program
During 2018, safety data expected to increase 10-fold
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Inclisiran emerging from Phase II with a “one size fits all” dosing regimen:
- 300mg s.c. dose on day 1, 90, then every 180 days
- Applicable to all patient populations and sub-groups