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 full time employee of The Medicines Company receiving salary and stock options 2
Inclisiran clinical trials program Inclisiran development ahead of schedule 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 3
RNAi therapeutics A new class of innovative medicines Harness natural catalytic mechanism A C A G A U U U A G C A U C U C A U U ≡ = ≡ = = = = = ≡ ≡ = = ≡ = ≡ = = = 1. RISC U G U C U A A A U C G U A G A G U A A T T Nobel Prize-winning science P Loading 5. Catalytic 4. Target Silence any gene in genome RISC Cleavage Mechanism RNA-induced mRNA Silencing Complex Potent and durable mechanism of action A C A G A U U U A G C A U C U C A U U (RISC) ≡ = ≡ = = = = = ≡ ≡ = = ≡ = ≡ = = = U G U C U A A A U C G U A G A G U A A T T 2. Sense P Antisense strand Strand Product engine for sustainable pipeline Removal 3. Target Watson-Crick Recognition base pairs Reproduced with permission from Alnylam Pharmaceuticals 4
ORION-1: Dose finding study in ASCVD and ASCVD risk equivalents Effect of two starting doses of inclisiran 300 mg vs. placebo s.c. Starting Maintenance Next dose day 450 10 Mean percent change ( ± 95% CI) Placebo s.c. 0 -10 -20 6-months time-averaged -30 LDL-C reduction = 51% -40 Inclisiran 300 mg s.c. -50 -60 0 30 60 90 120 150 180 210 240 270 300 330 360 Days from first injection 1. Ray KK et al. NEJM 2017; 376: 1430-40 Ray et al. N Engl J Med 2017; 376:1430-1440 5
ORION-1: Dose finding study in ASCVD and ASCVD risk equivalents LDL-C and PCSK9 reduction at day 180 after two starting doses Group Mean Mean Subgroup N LDL-C reduction 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 6
ORION-1: Dose finding study in ASCVD and ASCVD risk equivalents No safety concerns in any patient group at any dose 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 Ray et al. N Engl J Med 2017; 376:1430-1440 7
ORION-2: HoFH Pilot study Standard dose 300mg Day 1 and 90 Subject #2 Subject 2 40 Asp227Glu/Asp227Glu variant 20 0 0 50 100 150 200 Previous non-responder to mAbs -20 No observed LDL-C reduction despite -40 consistent and durable PCSK9 reduction -60 -80 Days LDL-C PCSK9 Lp(a) 8
ORION-2: HoFH Pilot study Standard dose 300mg Day 1 and 90 Subject #3 Subject 3 30 20 Asp227Glu/Val429Met variant 10 0 0 50 100 150 200 250 300 350 -10 LDL-C reduction: -20 • 16.7% at day 60 -30 • 32.8% at day 120 -40 -50 • 30.5% at day 180 -60 • 19.6% at Day 300 -70 -80 Days LDL-C PCSK9 Lp(a) 9
ORION-2: HoFH Pilot study Standard dose 300mg Day 1 and 90 Subject #4 Subject 4 20 10 Asp227Glu/Asp227Glu variant 0 0 50 100 150 200 250 300 350 -10 LDL-C reduction -20 • 29.5% at day 60 -30 -40 • 44.3% at day 120 -50 • 38.8% at day 180 -60 • 24.9% at Day 300 -70 -80 Days LDL-C PCSK9 Lp(a) 10
ORION-7: Renal impairment study No dose adjustments needed for impaired renal function Plasma PK over the first 48 hours PD effects on PCSK9 not significantly different 0 Exposure with renal dysfunction – as anticipated Normal inclisiran not detectable in any group after 48 hours Mild Percent change in PCSK9 -20 Moderate Severe -40 Group Cmax AUC -60 ng/mL h*ng/mL Normal 421 7,600 -80 Mild 987 11,800 -100 Moderate 897 13,433 0 10 20 30 40 50 60 Days Severe 1,756 19,214 11
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 1,617 equivalent patients (LDL-C >100 mg/dL) 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 • Additional clinical pharmacology studies for hepatic, renal impairment and for TQT • Pediatric studies 12
HPS-4/TIMI 65/ORION-4: CVOT study Planned study design Aims Primary endpoint To assess the effect of inclisiran on major Composite of major adverse cardiovascular events cardiovascular events (MACE), defined as: The study will randomize ≥15,000 • Coronary (CHD) death; or participants aged ≥55 years with pre - • Myocardial infarction; or existing cardiovascular disease between • Fatal or non-fatal ischaemic stroke; or inclisiran sodium 300 mg and matching • Urgent coronary revascularization placebo for a median of about 5 years. procedure 13
Inclisiran clinical trials program During 2018, safety data expected to increase 10-fold Rapid accumulation of safety data Patient-years exposure to • 5 patient-years on inclisiran per day inclisiran 2360 10-fold increase during 2018 • 1,800 with 3 doses • 300 with 4 – 5 doses 230 26 Phase I Phase II End of 2018 14
Inclisiran clinical trials program Inclisiran dosing regimen is simple, consistent and convenient 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 Consistent and durable efficacy No safety signals observed in a broad range of patient groups Future trials will evaluate inclisiran in other patient populations including pediatric subjects >8 years of age 15
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