NCT02576639

Dose-ranging Safety and Tolerability Study in Subjects ≥60 Years of Age

Completed Phase 2 Results posted Last updated 11 August 2017

What this trial tests

Phase 2 trial testing CNP520 in Alzheimer's Disease in 124 participants. Completed in 11 March 2016.

Timeline

10 August 2015

Primary endpoint
11 March 2016

11 March 2016

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	basic science
Enrollment	124
Start date	10 August 2015
Primary completion	11 March 2016
Estimated completion	11 March 2016
Sites	11 locations across Netherlands, Belgium, United Kingdom, Germany, United States

Drugs / interventions tested

• CNP520 — full drug profile →
• Placebo

Conditions studied

• Alzheimer's Disease — all drugs for Alzheimer's Disease →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 60 to 80, any sex, with Alzheimer's Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Subjects With Non-serious and Serious Adverse Events (AEs) and Deaths Primary · 13 weeks

Safety monitoring was conducted throughout the study.

Non-serious AEs

Group	Value	95% CI
Placebo	18
CNP520 2 mg	19
CNP520 10 mg	22
CNP520 35 mg	20
CNP520 85 mg	18

Serious AEs

Group	Value	95% CI
Placebo	0
CNP520 2 mg	0
CNP520 10 mg	0
CNP520 35 mg	1
CNP520 85 mg	0

Deaths

Group	Value	95% CI
Placebo	0
CNP520 2 mg	0
CNP520 10 mg	0
CNP520 35 mg	0
CNP520 85 mg	0

Change From Baseline of Amyloid Beta (Aβ) 1-38 , Aβ 1-40 and Aβ 1-42 Cerebrospinal Fluid (CSF) Concentrations Secondary · Day 92

CSF samples were collected by lumbar puncture for assessment.

Aβ 1-38

Group	Value	95% CI
Placebo	-2.34	± 6.969
CNP520 2 mg	-20.55	± 10.475
CNP520 10 mg	-62.48	± 6.202
CNP520 35 mg	-82.93	± 4.378
CNP520 85 mg	-89.5	± 1.676

Aβ 1-40

Group	Value	95% CI
Placebo	-2.64	± 6.598
CNP520 2 mg	-22.64	± 9.937
CNP520 10 mg	-62.89	± 6.485
CNP520 35 mg	-83.16	± 4.227
CNP520 85 mg	-90.69	± 1.651

Aβ 1-42

Group	Value	95% CI
Placebo	-2.58	± 5.189
CNP520 2 mg	-23.93	± 8.987
CNP520 10 mg	-64.28	± 6.086
CNP520 35 mg	-82.35	± 5.474
CNP520 85 mg	-89.68	± 2.32

Summary of Plasma PK Parameter: Cmax Secondary · Days 1, 91

Cmax = the observed maximum plasma concentration following drug administration. Blood samples were collected to assess Cmax. The PK analysis set was used for the analysis.

Day 1 (n=25,25,26,24)

Group	Value	95% CI
CNP520 2 mg	4.76	± 2.92
CNP520 10 mg	21.3	± 6.67
CNP520 35 mg	75.6	± 23.4
CNP520 85 mg	163	± 47.4

Day 91 (=23,22,24,20)

Group	Value	95% CI
CNP520 2 mg	16.6	± 5.51
CNP520 10 mg	81	± 29.2
CNP520 35 mg	237	± 65.7
CNP520 85 mg	602	± 150

Summary of Plasma PK Parameter: AUCtau Secondary · Days 1 and 91

AUCtau = the area under the plasma concentration-time curve from zero to the end of the dosing interval tau. Blood samples were collected to assess AUCtau.

Day 1 (n=25,25,26,24)

Group	Value	95% CI
CNP520 2 mg	67.1	± 60.7
CNP520 10 mg	278	± 65.7
CNP520 35 mg	966	± 214
CNP520 85 mg	2300	± 479

Day 91 (n=23,22,24,20)

Group	Value	95% CI
CNP520 2 mg	313	± 117
CNP520 10 mg	1500	± 476
CNP520 35 mg	4450	± 1090
CNP520 85 mg	11200	± 3320

Summary of Plasma PK Parameter: Tmax Secondary · Days 1 and 91

Tmax = the time to reach the maximum concentration after drug administration. Blood samples were collected to assess Tmax.

Day 1 (n=25,25,26,24)

Group	Value	95% CI
CNP520 2 mg	2.5	2.45 – 9
CNP520 10 mg	2.5	2.5 – 6.02
CNP520 35 mg	2.5	2.48 – 9
CNP520 85 mg	2.5	2.42 – 12

Day 91 (n=23,22,24,20)

Group	Value	95% CI
CNP520 2 mg	2.5	0 – 12.1
CNP520 10 mg	2.5	0 – 12.5
CNP520 35 mg	2.5	0 – 12
CNP520 85 mg	2.5	0 – 12

Summary of Plasma PK Parameter: Tlag Secondary · Days 1 and 91

Tlag = time delay between drug administration and first observed concentration above the lower limit of quantification (LOQ) in plasma . Blood samples were collected to assess Tlag.

Day 1 (n=25,25,26,24)

Group	Value	95% CI
CNP520 2 mg	0.5	0 – 0.567
CNP520 10 mg	0.5	0 – 2.5
CNP520 35 mg	0.5	0 – 0.55
CNP520 85 mg	0	0 – 2.5

Day 91 (n=23,22,24,20)

Group	Value	95% CI
CNP520 2 mg	0	0 – 0
CNP520 10 mg	0	0 – 0
CNP520 35 mg	0	0 – 0
CNP520 85 mg	0	0 – 0

Summary of Plasma PK Parameter: T1/2 Secondary · Day 91

T1/2 = the terminal elimination half-life. Blood samples were collected to assess T/12.

Group	Value	95% CI
CNP520 2 mg	150	± 52.2
CNP520 10 mg	155	± 40.9
CNP520 35 mg	155	± 33.9
CNP520 85 mg	160	± 22

Summary of PK Parameter: CLss/F Secondary · Day 91

CLss/F = the apparent systemic clearance from plasma observed during a dosing interval at steady state following extravascular administration. Blood samples were collected to assess CLss/F.

Group	Value	95% CI
CNP520 2 mg	7620	± 2620
CNP520 10 mg	7380	± 2480
CNP520 35 mg	8460	± 2790
CNP520 85 mg	8220	± 2270

Summary of Plasma PK Parameter: Racc Secondary · Day 91

Racc = the accumulation ratio . Blood samples were collected to assess Racc.

Group	Value	95% CI
CNP520 2 mg	5.86	± 2.25
CNP520 10 mg	5.33	± 1.05
CNP520 35 mg	4.75	± 1.16
CNP520 85 mg	5.02	± 1.47

Summary of CSF PK Concentrations Secondary · Days 1, 14, 28, 42, 56, 70 and 91

CSF samples were collected by lumbar puncture for assessment.

Day 1 (n=24,25,26,24)

Group	Value	95% CI
CNP520 2 mg	0	± 0
CNP520 10 mg	0	± 0
CNP520 35 mg	0	± 0
CNP520 85 mg	0	± 0

Day 14 (n=3,4,4,4)

Group	Value	95% CI
CNP520 2 mg	0.166	± 0.103
CNP520 10 mg	1.07	± 0.225
CNP520 35 mg	3.82	± 0.868
CNP520 85 mg	8.13	± 2.7

Day 28 (n=5,2,7,5)

Group	Value	95% CI
CNP520 2 mg	0.303	± 0.0731
CNP520 10 mg	1.48	± 0.106
CNP520 35 mg	4.48	± 1.02
CNP520 85 mg	12	± 4.12

Day 42 (n=3,6,5,5)

Group	Value	95% CI
CNP520 2 mg	0.314	± 0.0715
CNP520 10 mg	1.52	± 0.6
CNP520 35 mg	4	± 1.21
CNP520 85 mg	7.47	± 1.57

Day 56 (n=5,5,2,4)

Group	Value	95% CI
CNP520 2 mg	0.291	± 0.0605
CNP520 10 mg	1.28	± 0.177
CNP520 35 mg	5.03	± 2.69
CNP520 85 mg	8.04	± 5.69

Day 70 (n=6,5,6,4)

Group	Value	95% CI
CNP520 2 mg	0.231	± 0.149
CNP520 10 mg	1.04	± 0.212
CNP520 35 mg	4.62	± 0.753
CNP520 85 mg	8.71	± 0.71

Day 91 (n=23,21,24,20)

Group	Value	95% CI
CNP520 2 mg	0.305	± 0.099
CNP520 10 mg	1.44	± 0.431
CNP520 35 mg	4.52	± 0.946
CNP520 85 mg	10.4	± 3.26

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 0/24 (0%)

Deaths: —

CNP520 2mg

Serious: 0/25 (0%)

Deaths: —

CNP520 10mg

Serious: 0/25 (0%)

Deaths: —

CNP520 35mg

Serious: 1/26 (4%)

Deaths: —

CNP520 85mg

Serious: 0/24 (0%)

Deaths: —

Serious adverse events (1 terms)

Reaction	System	Placebo	CNP520 2mg	CNP520 10mg	CNP520 35mg	CNP520 85mg
Ankle fracture	Injury, poisoning and procedural complications	—	—	—	—	—

Other adverse events (155 terms — click to expand)

Reaction	System	Placebo	CNP520 2mg	CNP520 10mg	CNP520 35mg	CNP520 85mg
Headache	Nervous system disorders	—	—	—	—	—
Post lumbar puncture syndrome	Injury, poisoning and procedural complications	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—
Procedural pain	Injury, poisoning and procedural complications	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Flatulence	Gastrointestinal disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Procedural dizziness	Injury, poisoning and procedural complications	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—
Eye pruritus	Eye disorders	—	—	—	—	—
Vision blurred	Eye disorders	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Injection site pain	General disorders	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—
Laceration	Injury, poisoning and procedural complications	—	—	—	—	—
Post procedural discomfort	Injury, poisoning and procedural complications	—	—	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Somnolence	Nervous system disorders	—	—	—	—	—
Pollakiuria	Renal and urinary disorders	—	—	—	—	—
Dysphonia	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Ecchymosis	Skin and subcutaneous tissue disorders	—	—	—	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—	—	—	—
Pruritus generalised	Skin and subcutaneous tissue disorders	—	—	—	—	—

Most-reported serious reactions: Ankle fracture.

Data from ClinicalTrials.gov NCT02576639 adverse events section.

Sponsor's own description

The study determined the safety of CNP520 in healthy elderly over 3 months. Data relevant for Pharmacokinetic/Pharmacodynamic modeling were obtained in order to define the target dose in subsequent efficacy studies.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Drug candidates in clinical trials for Alzheimer's disease.
   Hung SY, Fu WM. · · 2017 · cited 281× · PMID 28720101 · DOI 10.1186/s12929-017-0355-7
2. A Close Look at BACE1 Inhibitors for Alzheimer's Disease Treatment.
   Das B, Yan R. · · 2019 · cited 142× · PMID 30830576 · DOI 10.1007/s40263-019-00613-7
3. Alzheimer's drug-development pipeline: 2016.
   Cummings J, Morstorf T, Lee G. · · 2016 · cited 78× · PMID 29067309 · DOI 10.1016/j.trci.2016.07.001
4. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs.
   Yan R. · · 2016 · cited 68× · PMID 27418961 · DOI 10.1186/s40035-016-0061-5
5. BACE1 Inhibitors for Alzheimer's Disease: The Past, Present and Any Future?
   Bazzari FH, Bazzari AH. · · 2022 · cited 58× · PMID 36557955 · DOI 10.3390/molecules27248823
6. Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics.
   Bhatia S, Singh M, Sharma P, Mujwar S, et al · · 2023 · cited 7× · PMID 37630283 · DOI 10.3390/molecules28166032
7. A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat.
   Vormfelde SV, Pezous N, Lefèvre G, Kolly C, et al · · 2020 · cited 6× · PMID 32583957 · DOI 10.1111/cts.12832
8. Recent advances in potential enzymes and their therapeutic inhibitors for the treatment of Alzheimer's disease.
   Vahid ZF, Eskandani M, Dadashi H, Vandghanooni S, et al · · 2024 · cited 1× · PMID 39717593 · DOI 10.1016/j.heliyon.2024.e40756