Safety, Tolerability and Efficacy of NPI-001 (AT-001) in Patients with Hereditary Cystatin C Amyloid Angiopathy (HCCAA)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arctic Therapeutics ehf.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Decision date (initial)

2023-08-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

European Innovation Commission Grant · Arctic Therapeutics ehf.

External identifiers

EU CT number

2023-503969-36-00

WHO UTN

U1111-1290-0255

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess safety and tolerability and efficacy of NPI-001 administered orally in HCCAA patients (ages 12 and over)
To assess the effect of NPI-001 on frequency of cerebral bleeding events in comparison with historical rate (HR)
To assess the effect of NPI-001 on biomarkers obtained from skin biopsies, including reduction in amyloid-cystatin C complexes and related collagen and skin cell surface activation markers compared with baseline levels, using cryoEM and Western blot approaches

Secondary objectives 7

1. To assess the effect of NPI-001 on the cognitive status
2. • To assess the effect of NPI-001 on death rates in comparison with HR
3. • To assess the effect of NPI-001 on amyloid cystatin C complex aggregation in plasma
4. • Assess the effect of NPI-001 on glutathione levels and GSSG/GSH ratios in plasma
5. • Assess the effect of NPI-001 on hCC levels in urine
6. • MRI-imaging to assess amyloid deposition in the brain
7. • To characterize pharmacokinetic parameters of NPI-001 in a subset of 5 participants with HCCAA

Conditions and MedDRA coding

Hereditary Cystatin C Amyloid Angiopathy (HCCAA)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Patient is male or female, aged 12 or older, and of Icelandic ancestry (see section 5.1 Selection of Trial Population). Subjects 12-17 years old will only qualify for inclusion if the DSMB approves lowering the minimum age following review of at least 3 months of safety in adults.
2. 2. Patient has been genotyped/sequenced and confirmed to carry the L68Q mutation in the cystatin C gene.
3. 3. Patient is willing to have a baseline and follow up skin biopsies according to the schedule of assessments, for up to 12 months.
4. 4. Patient is willing to have a baseline and follow up blood tests according to the schedule of assessments, for up to 12 months.
5. 5. Patient is willing to undergo MRI evaluations of the brain.
6. 6. Patient has provided informed consent for participation in trial
7. 7. Patient is willing and able to use contraception consistent with local regulations regarding the methods for participants in the clinical trial. Both female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a bilateral oophorectomy, hysterectomy or bilateral salpingectomy; must abstain from intercourse; or must agree to practice 2 acceptable methods of contraception throughout the course of the study and 4 weeks after the last visit. Acceptable methods of contraception include hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom), tubal ligation, and vasectomy.
8. 2.3. Patients with mild cognitive impairment with cognitive function to follow the study protocol.

Exclusion criteria 10

1. 1. Patient does not have L68Q mutation
2. 2. Patient has clinically significant illness, mental or physical, that, in the opinion of the investigator, might confound the results of the study, pose additional risk to the patient by their participation, or prevent/impede the patient from completing the study.
3. 3. Patient has known sensitivity to NAC
4. 4. Subject is not willing to cease NAC supplementation at least 2 weeks prior to study participation.
5. 5. Patient is pregnant or breastfeeding.
6. 6. Known or suspected excessive alcohol or drug abuse
7. 7. There is any concern by the investigator regarding the patient’s safety, compliance, or suitability with respect to his/her participation in the study.
8. 8. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 14 days, whichever is longer
9. 1.2. Patients with moderate to severe cognitive impairment.
10. 10. Patient is taking medications known to affect or be affected by CYP enzymes or transporters will be excluded to avoid any inference

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety • Treatment-Emergent Adverse Events and Serious Adverse Events, vital signs, ECG, physical and neurological examination, safety laboratory blood and urinalysis
2. Efficacy • Skin deposition of cystatin C/amyloid protein complex, including monomer vs dimer (and other high-molecular versions of same) ratios, together with skin collagen deposition and cell surface marker activation (vimentin, SMAD/WNT-1) which are correlated
3. Serious cerebral bleedings events

Secondary endpoints 7

1. • Clinical Dementia Rating (CDR) Scale
2. • Deaths
3. • Levels of cystatin C/amyloid dimers/oligomiers/polymers vs monomers of same
4. • Levels of glutathione and GSSG/GSH ratios in plasma
5. • hCC levels in urine
6. Plasma concentrations of NPI-001
7. • Change in amyloid deposition in the brain

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arctic Therapeutics ehf.

Sponsor organisation

Arctic Therapeutics ehf.

Address

Brekkubaer 24

City

Reykjavik

Postcode

110

Country

Iceland

Scientific contact point

Organisation

Arctic Therapeutics ehf.

Contact name

Ivar Hakonarson

Public contact point

Organisation

Arctic Therapeutics ehf.

Contact name

Ivar Hakonarson

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications