Lipids & metabolic liver disease
PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial
Authors' conclusion
This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations.
Study context
- Population
- Adults with established atherosclerotic CVD (aged ≥40 years) or at high risk (aged >50 years), LDL-C ≥1.8 mmol/L, on maximum tolerated statins and stable lipid-lowering therapy; 42 sites in 7 countries; mean age 64.3 years, 31% womenall randomised analysed
- Participants
- 267 adults
- Comparison
- Oral NNC0385-0434 (15 mg, 40 mg or 100 mg once daily) vs placebo or open-label SC evolocumab 140 mg every 2 weeks
- NNC0385-0434 15 mgn = 53
- NNC0385-0434 40 mgn = 53
- NNC0385-0434 100 mgn = 53
- Placebon = 54reference
- Evolocumabn = 54
- Primary endpoint
- Percentage change from baseline in LDL-C measured by β quantification
- Follow-up
- Week 12
Methodological detailsdouble-blind, placebo-controlled, active-controlled, phase 2, multicentre
- Double-blind
- Placebo-controlled
- Active-controlled
- Phase 2
- Multicentre
Primary result
As reported in the abstract
Reduction
32.0 percentage points
95% CI 20.9–43.0P < 0.0001
NNC0385-0434 15 mg · greater LDL-C reduction with NNC0385-0434 15 mg
Reduction
44.9 percentage points
95% CI 33.8–56.0P < 0.0001
NNC0385-0434 40 mg · greater LDL-C reduction with NNC0385-0434 40 mg
Reduction
61.8 percentage points
95% CI 50.7–72.9P < 0.0001
NNC0385-0434 100 mg · greater LDL-C reduction with NNC0385-0434 100 mg
Further findings
| Outcome | Evolocumab | NNC0385-0434 100 mg | Estimated treatment difference (percentage points) (95% CI) | |
|---|---|---|---|---|
| LDL-C decrease from baseline, evolocumabvs NNC0385-0434 100 mg · week 12Greater LDL-C reduction with evolocumab | 59.6% (SE 4.1) | 56.2% (SE 4.0) | 3.4 (−7.8 to 14.7) | |
| −1001020Difference, percentage points (linear scale) |
LDL-C decrease from baseline, evolocumab vs NNC0385-0434 100 mg · week 12
- Similar LDL-C reductions with evolocumab and NNC0385-0434 100 mg
Safety
Adverse events
- COVID-19 (most frequent AE), similar across groups
- 31 (12%) of 267
- Gastrointestinal disorders (most frequent treatment-related AE), three NNC0385 cohorts
- 26 patients and 35 events
- Gastrointestinal disorders, placebo and evolocumab
- one patient and one event each
- Deaths or treatment-related serious AEs
- 0
Original publication
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