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 hf.

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]

Trial duration

26 Mar 2024 → ongoing

Decision date (initial)

2024-02-28

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

2023-503969-36-01

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

Secondary objectives 8

1. • 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
2. • To assess the severity of cerebral bleeding
3. - To characterize pharmacokinetic parameters of NPI-001 in a subset of 5 participants with HCCAA after initial dosing of 250mg and after receiving the 750mg dose in steady state. If fewer than 5 participants are participating in the PK subset, additional participants will be recruited in an additional PK cohort to receive a single dose of 250 mg and a single dose of 750 mg.
4. • To assess the effect of NPI-001 on the cognitive status
5. • To assess the effect of NPI-001 on amyloid cystatin C complex aggregation in plasma
6. • Assess the effect of NPI-001 on glutathione levels and GSSG/GSH ratios in plasma
7. • Assess the effect of NPI-001 on hCC levels in urine
8. • To assess the effect of NPI-001 on death rates in comparison with HR

Conditions and MedDRA coding

Hereditary Cystatin C Amyloid Angiopathy (HCCAA)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

There are no plans to share individual participants data

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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. Patient has been genotyped/sequenced and confirmed to carry the L68Q mutation in the cystatin C gene.
3. Patients with previously established cystatin C/amyloid protein complexes in the skin
4. Patients with mild cognitive impairment with cognitive function to follow the study protocol.
5. Patient is willing to have a baseline and follow up skin biopsies according to the schedule of assessments, for up to 12 months, and up to 24 months if participating in the extension phase. *(N/A for patients participating in the additional PK cohort only)
6. Patient is willing to have a baseline and follow up blood tests according to the schedule of assessments, for up to 12 months, and up to 24 months if participating in the extension phase. *(N/A for patients participating in the additional PK cohort only)
7. Patient is willing to undergo MRI evaluations of the brain. *(N/A for patients participating in the additional PK cohort only)
8. Patient has provided informed consent for participation in trial.
9. 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.

Exclusion criteria 11

1. Patient does not have L68Q mutation
2. Patient is taking medications known to affect or be affected by CYP enzymes or transporters will be excluded to avoid any inference
3. 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.
4. Patient has known sensitivity to NAC
5. Subject is not willing to cease NAC supplementation at least 2 weeks prior to study participation.
6. Patient is pregnant or breastfeeding.
7. Known or suspected excessive alcohol or drug abuse
8. There is any concern by the investigator regarding the patient’s safety, compliance, or suitability with respect to his/her participation in the study.
9. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 14 days, whichever is longer
10. Patients with moderate to severe cognitive impairment.
11. Coagulation/clotting parameters clinically significant outside the normal range (platelet counts, aPTT, PT

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety • Treatment-Emergent Adverse Events and Serious Adverse Events, vital signs, ECG, physical and neurological examination, safety laboratory blood and urinalysis after a single dose of 250 mg and 750 mg of NACA (PK cohort), 12 months of treatment (main study) and after 24 months of treatment (OLE phase)
2. Efficacy • Frequency of clinical cerebral bleedings events, defined as any bleed that causes stroke, hemorrhagic or ischemic after 12 months of treatment (main study) and after 24 months of treatment (OLE phase)

Secondary endpoints 8

1. • Clinical Dementia Rating (DSR-2) 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 PK parameters: Cmax, Tmax and AUC0-24h and T1/2 for single dose of 250mg or 750mg (and steady state for subjects participating in the main study)
7. • 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
8. • (1) Clinical impact in terms on speech, paralysis and how quickly symptoms reverse (2) CT scan to assess size, distribution and resolution of hemorrhage 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 hf.

Sponsor organisation

Arctic Therapeutics hf.

Address

Bjargargata 1

City

Reykjavik

Postcode

102

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

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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